An efficient synthesis and antimicrobial evaluation of 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles

Article abstract of DOI:10.24820/ark.5550190.p010.760

The cyclodehydration of O-acylamidoximes at room temperature in the superbase system KOH/DMSO represents a simple and efficient way to 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles. This method is suitable for the preparation of 5-(4-vinylphenyl)-1,2,4-oxadia

Full text of DOI:10.24820/ark.5550190.p010.760

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Arkivoc 2018, part vii, 0-0
An efficient synthesis and antimicrobial evaluation of 5-alkenyl- and 5-styryl-
1,2,4-oxadiazoles
Marina Tarasenko,*a Vera Sidneva,a Alexandra Belova,b Anna Romanycheva,b Tatyana Sharonova,с Sergey
Baykov,c Anton Shetnev,b Eugeniy Kofanov,a and Mikhail A. Kuznetsovc
aDepartment of Organic and Analytical Chemistry, Yaroslavl State Technical University, Yaroslavl, Russian
Federation
bPharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, Yaroslavl,
Russian Federation
cInstitute of Chemistry, Saint Petersburg State University, Saint Petersburg, Russian Federation
Email: mkarunnaya@mail.ru
Received 09-20-2018
Accepted 12-03-2018
Published on line 12-27-2018
Abstract
The cyclodehydration of O-acylamidoximes at room temperature in the superbase system KOH/DMSO
represents a simple and efficient way to 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles. This method is suitable for
the preparation of 5-(4-vinylphenyl)-1,2,4-oxadiazoles as well. Results of the antimicrobial tests demonstrated
that the synthesized compounds exhibit a moderate antimicrobial effect against E.coli, S.aureus and C.albicans
strains.
Keywords: Heterocycles, O-acylamidoximes, cyclodehydration, base catalysis, antimicrobial activity
DOI: https://doi.org/10.24820/ark.5550190.p010.760
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Introduction
3,5-Disubstituted-1,2,4-oxadiazoles are widely used both in pharmaceutical research and for the development
of new materials.1-4 In particular, compounds bearing a carbon-carbon double bond in the 5-position of the
heterocyclic ring are agonists of the central nicotinic acetylcholine receptors5, PDE-4 inhibitors6-8, non-
nucleoside antivirals9, antiplasmodials10 and antiproliferative agents (Fig. 1).11 Moreover, 5-alkenyl- and 5-
styryl-1,2,4-oxadiazoles are actively employed in organic synthesis, including Michael addition reactions12-14
1,3-dipolar cycloadditions15, 16, Rh-catalyzed 17, 18 or metal-free arylations.19
,
Figure 1. Examples of biologically active 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles.
Most of the traditional methods for the preparation of 1,2,4-oxadiazole, such as condensation of
amidoximes with carboxylic acids and their derivatives or 1,3-dipolar cycloadditions of nitrile oxides to nitriles,
20-23 require harsh conditions (high temperature, microwave irradiation or high pressure).24, 25 These conditions
pose a serious limitation for labile organic compounds, especially those containing C=C double bonds and
typically yield multiple side-products along with low yields of target compounds.26-30 For this reason, novel
synthetic approaches to 1,2,4-oxadiazoles, operating under mild conditions, have been actively developing in
recent years.31-33
Previously, we have reported that the MOH/DMSO (M = Li, Na, K) system is an efficient medium for the
synthesis of 1,2,4-oxadiazoles at ambient temperature.34-37 While many substrates with aliphatic, aromatic
and heterocyclic substituents have been studied, those with alkenyl and styryl groups were not. Herein, we
describe an efficient and practical cyclodehydration of O-acylamidoximes with alkenyl- and styryl- moieties
that occurs in KOH/DMSO medium.
Results and Discussion
Synthesis of 5-alkenyl- and 5-styryl-1,2,4-oxadiazoles (4)
The starting O-acylamidoximes (3a-p) were synthesized from commercial nitriles in two steps (Scheme 1).
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Scheme 1: Synthetic scheme for generation of the O-acylamidoximines (3a-p)
The O-acylamidoximes 3a-p were then converted to the corresponding substituted 1,2,4-oxadiazoles in
generally good yields under mild conditions (Scheme 2 and Table 1).
Scheme 2: Synthetic scheme for generation of the corresponding substituted-1,2,4-oxadiazpless from the
corresponding O-acylamidoximines (3a-p)
At the onset of our study, we investigated the cyclodehydration of the acrylic acid derivative 3a (Table 1,
entries 1 and 2). Initially, an equimolar ratio of the O-acylamidoxime and KOH was used38, and the reaction
was carried out for 10 minutes. The targeted 5-vinyl-1,2,4-oxadiazole is a colorless liquid. 26-30The isolated
white powder contained no carbon-carbon double bond according to the IR spectrum. Moreover, the
molecular weight of this solid is ~450 kDa (by GPC), suggesting that the material formed is a product of the
base-initiated anionic polymerization (anionic polymerization of Michael acceptors in DMSO is known) 39, 40
Reducing the amount of KOH to 0.1 equiv. decreases the reaction rate and allows isolation of the desired
4a after column chromatography, albeit in low (11%) yield (Table 1, entry 2). Similar results were obtained for
the methacrylic derivative 3b (Table 1, entries 3 and 4). On the contrary, crotonic and methylcrotonic
derivatives 4c and 4d were obtained in good yields (79 and 80%, respectively) with 0.1 equiv. of KOH (Table 1,
entries 6 and 8). The cyclodehydration of O-acylamidoximes 3e-n was successful with 1 equiv. of KOH (with
the single exception of 3k), furnishing good to excellent yields of desired 1,2,4-oxadiazoles (Table 1, entries 9-
21). Our results demonstrate that the presence of alkyl, aryl or heteroaryl substituents at the terminal carbon
atom of the double bond reduces the polymerization tendency of 1,2,4-oxadiazoles.
Furthermore, we applied our protocol for the preparation of 5-(4-vinylphenyl)-1,2,4-oxadiazoles. These
compounds are only poorly studied, presumably because their synthesis is rather tedious and given that the
vinyl group is unstable under thermal cyclodehydration conditions.41 For this reason, alternative approaches
such as the Wittig and Stille reactions or the reduction of the appropriate alkyne41,42 were utilized for the
synthesis of 1,2,4-oxadiazoles with vinylphenyl moiety. Noteworthy, compounds 4o and 4p were prepared in
good yields according to our method (Table 1, entries 22 and 23).
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Table 1. Results of cyclodehydration of O-acylamidoximes (3a-p) to the corresponding oxadiazoles (4a-p).
Amount of Reaction
Yield,
%
-
11
-
15
-
79
-
80
Entry O-acylamidoxime
R1
R2
Product
4a
КОН
1.0
0.1
1.0
0.1
1.0
0.1
1.0
0.1
time, min
1
10
30
10
30
10
30
10
30
3a
3b
3c
3d
2
3
4
5
4b
4c
6
7
8
4d
9
3e
3f
1.0
1.0
1.0
1.0
10
10
10
10
4e
4f
87
88
80
82
10
11
12
3g
3h
4g
4h
13
14
3i
3j
1.0
1.0
10
10
4i
4j
80
79
15
16
17
18
19
20
1.0
0.1
1.0
0.1
1.0
0.1
10
60
10
60
20
60
4k
4k
4l
4l
4m
4m
35
85
78
78
86
95
3k
3l
3m
3n
3o
21
22
23
1.0
1.0
1.0
10
10
10
4n
4o
4p
74
88
85
3p
A broad spectrum of compounds based on the 1,2,4-oxadiazole scaffold are well known as potent
antimicrobial agents.43 No antibacterial studies of 1,2,4-oxadiazoles containing a C=C double bond, however,
have, hitherto, been conducted. Motivated by this, we assessed the antibacterial and antifungal activities of
synthesized heterocycles against Staphylococcus aureus, Escherichia coli, and Candida albicans by the broth
double microdilution method.44,45
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Biological activity
The antimicrobial activity was determined in vitro by broad-dilution method against strains of S. aureus (ATCC-
25923), E. coli (С 600) and C. albicans (SC5314)46.
The experimental data revealed that all of the tested 1,2,4-oxadiazoles exhibited low to medium activity
against both Gram-positive and Gram-negative bacterial strains (Table 2).
Table 2. MIC values in µg/mL µmol/mL for compounds 4d-g and 4j-p against various bacterial strains and
fungi.
Gram-negative
Gram-positive
Fungi
E. coli
S. aureus
C. albicans
Entry
Compound
MIC,
µg/mL
215
MIC,
mM
1,07
1,07
MIC,
µg/mL
215
MIC,
mM
1,07
0,86
MIC,
µg/mL
146
MIC,
mM
0,73
1
2
4d
4e
267
213
>181
>0,73
3
4
4f
304
299
1,07
1,07
304
299
1,07
1,07
>207
>0,73
>0,73
4g
>203
5
6
7
8
9
10
11
12
13
14
4i
4j
4k
4l
4m
4n
4o
331
331
288
>584
288
>533
267
304
0,147
-
1,07
1,07
1,07
>2,14
1,07
>2,14
1,07
1,07
0,0003
-
331
331
288
>584
288
>533
267
304
148
1,07
1,07
1,07
>2,14 >199
1,07 >196
>2,14 >182
1,07
1,07
0,003
-
>225
225
>196
>0,73
0,73
>0,73
>0,73
>0,73
>0,73
>0,73
>0,73
-
>181
>207
-
4p
Pefloxacin
Fluconazole
-
149
0,0032
The screening set included twelve compounds (4d-g and 4i-p). Three synthesized 1,2,4-oxadiazoles (4a-4c)
were too unstable at assay conditions, while 4h was insoluble in the assay medium. Therefore these
compounds were excluded from the study. Pefloxacin and Fluconazole were used as reference standards for
the comparison of antimicrobial activity. The minimum inhibitory concentration (MIC) for all compounds was
determined. The experimental data (Table 2) revealed that all tested 1,2,4-oxadiazoles exhibit low to medium
activity against both Gram- positive and Gram-negative bacterial strains.
The most active 1,2,4-oxadiazole 4e showed bacteriostatic effect with MIC 0.86 mM (213 μg/ml) against
Staphylococcus aureus (ATCC-25923) and bacteriostatic effect with MIC 1.07 mM (267 μg/ml) against
Escherichia coli (C-600). Other 1,2,4-oxadiazoles showed moderate to weak MIC against all tested bacteria.
While compound 4l bearing a furan ring displayed no antimicrobial activity in all tests, thiophene derivative 4k
demonstrated moderate activity. Two 1,2,4-oxadiazoles (4d and 4i) showed medium fungistatic effect
inhibiting the growth of Candida albicans (NCTC 885-653) with MIC 0.73 mM (146-225 µg/ml respectively),
which is, however, less potent than the standard drug Fluconazole (1 μg/ml against Candida albicans)50.
Overnight cultures were grown at 37 °C in Lysogeny broth (LB) and diluted to obtain an opacity equivalent
to 0.5 on the McFarland scale. The compounds are weighed and dissolved in DMSO to give concentrations
equal to 20.7 µmol/mL. The pefloxacin and miconazole were used to antimicrobial standard. The
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concentration of 2.07 µmol/mL was used as the starting one, providing a final concentration equal to 0.03
µmol/mL. The tubes were incubated for 12 h at 37 °C. Growth inhibition detection was considered as positive
results. It was verified that DMSO as completely inactive against the tested microorganisms in the less than 10
% concentrations. A series of tubes is prepared by mixing one part of each dilution of the compound with
some parts of the LB, previously inoculated and incubated for 24 h at 37 °C. All experiments were carried out
in triplicate. The MIC was considered the lowest drug concentration for which there is no microbial growth.
The most active 1,2,4-oxadiazole (4e) showed bacteriostatic effect with MIC 0.86 mM (213 μg/ml) against
Staphylococcus aureus (ATCC-25923), and bacteriostatic effect with MIC 1.07 mM (267 μg/ml) against
Escherichia coli (C-600). Other 1,2,4-oxadiazoles showed moderate to weak MIC against all tested bacteria.
While compound 4l bearing a furan ring displayed no antimicrobial activity in all tests, thiophene derivative 4k
demonstrated moderate activity. Two 1,2,4-oxadiazoles (4d and 4i) showed medium fungistatic effect
inhibiting the growth of Candida albicans (NCTC 885-653) with MIC 0.73 mM (146-225 µg/ml, respectively),
which is, however, less potent than the standard drug Fluconazole (1 μg/ml against Candida albicans).50
Conclusions
We have developed a simple, speedy and efficient method for the synthesis of 5-alkenyl- and 5-styryl-1,2,4-
oxadiazoles. A series of 16 compounds was obtained, 10 of which have not been previously reported in the
literature. The novel synthetic protocol offers several advantages, including short reaction times, high yields of
products, and simple work-up procedure. In addition, the twelve 1,2,4-oxadiazoles synthesized were
evaluated agaist both Gram-positive and Gram-negative bacteria strains as well as one fungi strain, and
displayed moderate antimicrobial activity.
Experimental Section
General. Starting O-acylamidoximes (3a-p) were synthesized from commercial nitriles in two steps (for more
details see Supplemental Materials). All other reagents and solvents, including DMSO, were purchased and
used without further purification. All reactions were conducted in an open flask.. Reactions were monitored by
analytical thin layer chromatography (TLC) Macherey-Nagel, TLC plates Silufol UV-254 using UV light for
detection. Column chromatography was carried out with silica gel grade 60 (0.040-0.063 mm) 230-400 mesh
with a hexane/ethyl acetate mixture as eluent (4/1). NMR spectra were recorded on Bruker Avance DPX 400
(400.13 MHz and 100.61 MHz for 1H and 13C, respectively) or on Bruker Avance III 500 MHz (500.03 MHz for 1H
and 125.73 MHz for 13C) in DMSO-d6 or in CDCl3. Chemical shifts are reported as parts per million (δ, ppm).
The solvent peaks were used as internal standards: 2.50 ppm for residual 1H, 39.50 ppm for 13C in DMSO-d6;
7.26 ppm for residual 1H, 77.16 ppm for 13C in CDCl3. Multiplicities are abbreviated as follows: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad and coupling constants, J, are reported in Hertz (Hz).
The signals of second-order proton systems AA’XX’ of the para-substituted and AA’XX’Y of the
monosubstituted phenyl rings are not seen clearly in the 1H NMR spectra, therefore, “apparent” coupling
constants for observed “doublets” and “triplets” of appropriate aromatic protons are provided. Melting points
were determined in open capillary tubes on Electrothermal IA 9300 series Digital Melting Point Apparatus.
High-resolution mass spectra (HRMS) were measured on Bruker Maxis HRMS-ESI-qTOF (ESI Ionization). IR
spectra were measured with an IRF Perkin Elmer Spectrum RX1 spectrometer using suspension in Nujol or as
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in thin films (microlayer) between KBr discs. Gel permeation chromatography was performed on DIONEX
UltiMate–3000 (column: l = 15 сm, d = 2 mm). A mixture of acetonitrile and water (1:4) was used as eluent.
“Th” is the abbreviation for the thiophen ring.
Synthesis and characterization of 1,2,4-oxadiazoles (4a-p). The corresponding O-acylamidoxime (3a-p) (1.5
mmol) was added to a suspension of powdered KOH (1.5 or 0.15 mmol, see Table 1) in DMSO (2 mL). The
reaction mixture was stirred at room temperature for a specified time (see Table 1). The reaction mixture was
diluted with cold water (20 mL), and resulted precipitate was filtered off, washed with cold water (25 mL) and
dried in air at room temperature.
3-Phenyl-5-vinyl-1,2,4-oxadiazole (4a).13 The compound was synthesized using 0.1 equiv of KOH for 0.5 h.
Yield after purification by column chromatography (ethyl acetate : hexane 1 : 4) was 11% (28 mg) of yellow oil.
IR (microlayer, νmax, cm–1): 1215 (С-О), 1593 (C=N), 1647 (СH=СH2). 1H NMR (400 MHz, DMSO-d6): δH 6.08
(1H, d, J 11 Hz, cis-НС=СН2), 6.53 (1H, d, J 18 Hz, tr-НС=СН2), 6.88 (1H, dd, J 18 Hz, 11 Hz, НС=С), 7.48-7.55 (3H,
m, m,p-H), 7.97-8.04 (2H, m, о-Н). 13C NMR (101 MHz, DMSO-d6): δC 120.7 (=CН2), 126.6 (i-C), 127.4 (m-С),
129.5 (о-С), 130.2 (-СН=), 131.9 (p-С), 168.4 (С-3), 174.9 (С-5). HRMS (ESI), m/z: calcd for C10H9N2O[M+H]+
173.0709, found 173.0701.
3-Phenyl-5-(prop-1-en-2-yl)-1,2,4-oxadiazole (4b). The compound was synthesized using 0.1 equiv of KOH for
0.5 h. Total yield after purification by column chromatography (ethyl acetate : hexane 1 : 4) was 15% (41 mg)
of yellow oil. IR (microlayer, νmax, cm–1): 1158 (С-О), 1578 (C=N), 1643 (СH2=С). 1Н NMR (400 MHz, DMSO-d6):
δH 2.22 (3Н, s, Me), 5.88 (1Н, s, =СН2), 6.28 (1Н, s, =СН2), 7.55-7.61 (3Н, m, m,p-H), 8.03 (2Н, d, J 7.9 Hz, o-H).
13C NMR (101 MHz, DMSO-d6): δC 18.9 (Me), 125.2 (СH2=), 125.9 (С=), 126.7 (i-C), 127.4 (m-C), 129.5 (o-C),
131.9 (p-С), 168.5 (С-3), 176.5 (С-5). HRMS (ESI), m/z: calcd for C11H11N2O [M+H]+ 187.0866, found 187.0860.
(E)-3-Phenyl-5-(prop-1-en-1-yl)-1,2,4-oxadiazole (4c). 17 The compound was synthesized using 0.1 equiv of
KOH for 0.5 h. Yield 79% (220 mg); yellow oil. IR (microlayer, νmax, cm–1): 1120 (С-О), 1562 (C=N), 1665
(СH=СH). 1Н NMR (500 MHz, CDCl3): δH 2.05 (3Н, dd, J 7.0, 2, Me), 6.50 (1H, dq, J 16.2, 2 Hz, Het-СН=), 7.18
(1H, dq, J 16.2, 7.0 Hz, Me-СН=), 7.49-7.52 (3Н, m, m,p-Н), 8.11 (2Н, d, J 8.2 Hz, о-Н). 13C NMR (125 MHz,
CDCl3): δC 18.8 (Me), 115.0 (Het-CH=), 127.0 (i-C), 127.4 (m-C), 128.8 (o-C), 131.0 (p-C), 142.8 (Ph-CH=), 168.4
(C-3), 174.7 (C-5). HRMS (ESI), m/z: calcd for C11H11N2O [M+H]+ 187.0866, found 187.0853.
5-(2-Methylprop-1-enyl)-3-phenyl-1,2,4-oxadiazole (4d). The compound was synthesized using 0.1 equiv of
KOH for 0.5 h. Yield 80% (240 mg); beige powder, mp 44-46 °С. IR, ν, cm–1: 841 (С=СН), 1152 (С-О), 1592 (C=N),
1656 (С=СH). 1Н NMR (500 MHz, CDCl3), δ 2.09 (d, J 1.0 Hz, Me, 3Н), 2.38 (d, J 1.0 Hz, Me, 3Н), 6.33 (sept, J 1.2
Hz, С=СН, 1Н), 7.49-7.52 (m, m,p-H, 3Н), 8.14 (m, o-H, 2Н). 13C NMR (125 MHz, CDCl3), δ 21.1 (Me), 27.6 (Me),
108.9 (С=СН), 127.3 (i-C), 127.4 (m-C), 128.8 (o-C), 130.9 (p-C), 154.3 (С=СН), 168.1 (C-3), 175.1 (C-5). HRMS
(ESI), m/z: calcd for C12H13N2O [M+H]+ 201.1022, found 201.1020.
(E)-3-Phenyl-5-(2-phenylethenyl)-1,2,4-oxadiazole (4е).19 Yield 87% (324 mg), white powder, mp 95-97 °С (Lit.
mp 95-97 °С). IR, ν, cm–1: 971 (tr-СН=СН), 1175 (С–O), 1593 (C=N), 1644 (СH=СH). 1Н NMR (400 MHz, DMSO-
d6): δH 7.45 (1H, d, J 16.4 Hz, Het-CH=), 7.43-7.49 (3H, m, m,p-H), 7.56-7.63 (3H, m, m,p-H), 7.85 (2H, m, o-H),
7.95 (1H, d, J 16.4 Hz, Ph-CH=), 8.05-8.09 (2H, m, o-H). 13C NMR (101 MHz, DMSO-d6): δC 110.7 (Het-CH=),
126.8 (i-C, 3-Ph), 127.5 (o-C, 5- Ph), 128.9 (m-C, 3- Ph), 129.5 (p-C, 5- Ph), 129.7 (m-C, 5- Ph), 131.1 (o-C, 3- Ph),
132.0 (p-C, 3- Ph), 134.7 (i-C, 5-Ph), 143.3 (Ph-CH=), 168.5 (C-3), 175.9 (C-5). HRMS (ESI), m/z: calcd for
C16H13N2O [M+H]+ 249.1022, found 249.1014.
5-[(E)-2-(4-Chlorophenyl)ethenyl]-3-phenyl-1,2,4-oxadiazole (4f).19 Yield 88% (373 mg), white powder, mp
1
158-160 °С (Lit. mp 154-156 °С). IR, ν, cm–1: 975 (tr-СН=СН), 1174 (С–O), 1573 (C=N), 1648 (СH=СH). Н NMR
(400 MHz, DMSO-d6): δH 7.50 (1H, d, J 16.5, Het-HC=), 7.55 (2H, d, J 8.5 Hz, m-H), 7.58-7.63 (3H, m, m,p-H),
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7.90 (2H, d, J 8.5 Hz, o-H), 7.96 (1H, d, J 16.5 Hz, Ph-HC=), 8.05-8.08 (2H, m, o-H). 13C NMR (101 MHz, DMSO-
d6): δC 111.5 (Het-CH=), 126.7 (i-C, 3-Ph), 127.5 (m-C, 3-Ph), 129.5 (o-C, 3-Ph), 129.7 (m-C, 5-Ph), 130.6 (o-C, 5-
Ph), 132.1 (p-C, 3-Ph), 133.7 (i-C, 5-Ph), 135.7 (p-C, 5-Ph), 141.9 (Ph-СH=), 168.5 (C-3), 175.7 (C-5). HRMS (ESI),
m/z: calcd for C16H12ClN2O [M+H]+ 283.0633, found 283.0632.
3-(4-Methoxyphenyl)-5-[(E)-2-phenylethenyl]-1,2,4-oxadiazole (4g).19 Yield 80% (333 mg), white powder, mp
122-123 °С (Lit. mp 130-132 °С). IR, ν, cm–1: 975 (tr-СН=СН), 1177, 1255 (С–O), 1556 (C=N), 1637 (СH=СH). 1Н
NMR (400 MHz, DMSO-d6): δH 3.85 (3H, s, OMe), 7.14 (2H, d, J 8.9 Hz, m-H), 7.43 (1H, d, J 16.5 Hz, Het-CH=),
7.46-7.50 (3H, m, m,p-H), 7.85-7.87 (2H, m, o-H), 7.94 (1H, d, J 16.5 Hz, Ph-CH=), 8.00 (2H, d, J 8.8 Hz, o-H). 13C
NMR (101 MHz, DMSO-d6): δC 55.9 (OMe), 110.8 (Het-CH=), 115.1 (m-C, 3-Ph), 119.1 (i-C, 3-Ph), 128.8 (o-C, 5-
Ph), 129.2 (o-C, 3-Ph), 129.5 (m-C, 5-Ph), 131.1 (p-C, 5-Ph), 134.8 (i-C, 5-Ph), 143.1 (Ph-CH=), 162.2 (p-C, 3-Ph),
168.2 (C-3), 175.6 (C-5). HRMS (ESI), m/z: calcd for C17H15N2O2 [M+H]+ 279.1128, found 279.1133.
3-(4-Methoxyphenyl)-5-[(E)-2-(4-methoxyphenyl) ethenyl]-1,2,4-oxadiazole (4h).19 Yield 82% (379 mg), white
powder, mp 112-114 °С (Lit. mp 123-125 °С). IR, ν, cm–1: 970 (tr-СН=СН), 1030, 1172, 1252 (С–O), 1598 (C=N),
1642 (СH=СH). 1Н NMR (400 MHz, DMSO-d6): δH 3.83 (6H, d, J 8.2 Hz, OMe), 7.03 (2H, d, J 8.5 Hz, m-H, 5-Ph),
7.12 (2H, d, J 8.9 Hz, m-H, 3- Ph), 7.24 (1H, d, J 16.4 Hz, Het-CH=), 7.80 (2H, d, J 8.8 Hz, o-H, 5-Ph), 7.86 (1H, d, J
16.4 Hz, Ph-CH=), 7.98 (2H, d, J 8.8 Hz, o-H, 3- Ph). 13C NMR (101 MHz, DMSO-d6): δC 55.9 (2 OMe), 108.1 (Het-
CH=), 115.0 (m-C, 3-Ph), 115.1 (m-C, 5-Ph), 119.2 (i-C, 3-Ph), 127.4 (i-C, 5-Ph), 129.1 (o-C, 3-Ph), 130.6 (o-C, 5-
Ph), 142.9 (Ph-CH=), 161.8 (p-C, 5-Ph), 162.1 (p-C, 3-Ph), 168.1 (C-3), 175.9 (C-5). HRMS (ESI), m/z: calcd for
C18H17N2O3 [M+H]+ 309.1234, found 309.1231.
5-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-3-phenyl-1,2,4-oxadiazole (4i). Yield 80% (369 mg), white powder,
mp 118-119 °С. IR, ν, cm–1: 966 (tr-СН=СН), 1039, 1266 (С–O), 1582 (C=N), 1646 (СH=СH). 1Н NMR (400 MHz,
DMSO-d6): δH 3.82 (3H, s, OMe), 3.86 (3H, s, OMe), 7.03 (1H, d, J 8.2 Hz, H-6, 5-Ph), 7.35 (1H, d, J 8.2 Hz, H-5, 5-
Ph), 7.36 (1H, d, J 16.5 Hz, Ar-CH=), 7.51 (1H, s, H-2, 5-Ph), 7.60 (3H, m, m,p-H, Ph), 7.87 (1H, d, J 16.5 Hz, Ph-
CH=), 8.06 (2H, m, o-H, Ph). 13C NMR (101 MHz, DMSO-d6): δC 56.1 (OMe), 56.2 (OMe), 108.2 (Het-CH=), 110.8
(CH, Ar), 112.1 (CH, Ar), 123.7 (CH, Ar), 126.9 (i-C, Ph), 127.5 (m-C, Ph), 127.6 (i-C, Ar), 129.7 (o-C, Ph), 131.9 (p-
C, Ph), 143.5 (Ar-CH=), 149.6 (C, Ar), 151.7 (C, Ar), 168.4 (C-3), 176.3 (C-5). HRMS (ESI) calcd for C18H17N2O3
[M+H]+ 309.1234, found 309.1238.
5-[(E)-2-(2,3-Dimethoxyphenyl)ethenyl]-3-phenyl-1,2,4-oxadiazole (4j). Yield 79% (365 mg), white powder,
mp 106-108 °С. IR, ν, cm–1: 975 (tr-СН=СН), 1071, 1269 (С–O), 1557 (C=N), 1630 (СH=СH). 1Н NMR (400 MHz,
DMSO-d6): δH 3.85 (6H, s, 2Me), 7.17 (2H, m, H-4,6, Ar), 7.41 (1H, d, J 16.5 Hz, Het-CH=), 7.51 (1H, m, H-5, Ar),
7.55-7.63 (3H, m, m,p-H), 8.05-8.10 (3H, m, o-H, Ph-CH=). 13C NMR (101 MHz, DMSO-d6): δC 56.3 (OMe), 61.4
(OMe), 111.7 Het-CH=), 115.6 (CH, Ar), 119.5 (CH, Ar), 124.9 (CH, Ar), 126.8 (i-C, Ph), 127.5 (m-C, Ph), 128.1 (i-
C, Ar), 129.7 (o-C, Ph), 132.0 (p-C, Ph), 137.4 (Ar-CH=), 148.3 (C, Ar), 153.2 (C, Ar), 168.5 (C-3), 176.0 (C-5).
HRMS (ESI), m/z: calcd for C18H17N2O3 [M+K]+ 347.0793, found 347.0794.
3-(4-Methylphenyl)-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole (4k). Yield 85% (342 mg), white
powder, mp 102-104 °С. IR, ν, cm–1: 954 (tr-СН=СН), 1160 (С–O), 1550 (C=N), 1629 (СH=СH). 1Н NMR(400 MHz,
DMSO-d6): δH 2.35 (3Н, s, Me), 6.98 (1Н, d, J 15.8 Hz, Het-СН=), 7.17 (1Н, dd, J 5.0,3.3 Hz, Th, H-4), 7.33 (2Н, d,
J 7.9 Hz, m-H), 7.63 (1Н, d, J 3.3 Hz,Th, H-3), 7.77 (1Н, d, J 5.0 Hz, Th, Н-5), 7.90 (2Н, d, J 7.9 Hz, o-H), 8.04 (1Н,
d, J 16.2 Hz, Th-СН=). 13C NMR (101 MHz, DMSO-d6): δC 21.5 (Me), 108.7 (Het-СН=), 124.0 (Th, C-4), 127.4 (o-
C), 129.1 (Th, C-3), 130.1 (m-C), 130.8 (i-C, Ph), 132.5 (Th, C-5), 135.8 (Th, C-2), 139.5 (p-C), 141.8 (Het-СН=),
168.4 (C-3), 175.3 (C-5). HRMS (ESI), m/z: calcd for C15H13N2OS [M+H]+ 269.0743, found 269.0751.
3-(4-Chlorophenyl)-5-[(E)-2-(furan-2-yl)ethenyl]-1,2,4-oxadiazole (4l). Yield 78% (319 mg), white powder, mp
115-116 °С. IR, ν, cm–1: 964 (tr-СН=СН), 1091, 1272 (С–O), 1528 (C=N), 1653 (СH=СH). 1Н NMR (400 MHz,
DMSO-d6): δH 6.71 (1H, dd, J 3.4, 1.8 Hz, Fur, H-4), 6.97 (1H, d, J 15.9 Hz, Het-CH=), 7.09 (1H, d, J 3.4 Hz, Fur, H-
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3), 7.66 (2H, d, J 8.5 Hz, m-H), 7.79 (1H, d, J 16.2 Hz, Fur-CH=), 7.95 (1H, m, Fur, H-5), 8.05 (5H, d, J 8.5 Hz, o-H).
13C NMR (101 MHz, DMSO-d6): δC 107.0 (Het-CH=), 113.6 (Fur, C-3), 117.2 (Fur, C-4), 125.6 (i-C, Ph), 129.3 (m-
C), 129.9 (o-C), 130.1 (Fur-CH=), 136.8 (p-C), 147.0 (Fur, C-5), 150.7 (Fur, C-2), 167.7 (C-3), 175.9 (C-5). HRMS
(ESI), m/z: calcd for C14H10ClN2O2 [M+H]+ 273.0425, found 273.0427.
3-(5-Methylthiophen-2-yl)-5-[(E)-2-phenylethenyl]-1,2,4-oxadiazole (4m). Yield 95% (382 mg), white powder,
mp 113-115 °С. IR, ν, cm–1: 974 (tr-СН=СН), 1098 (С–O), 1572 (C=N), 1643 (СH=СH). 1Н NMR (400 MHz, DMSO-
d6): δH 2.53 (3H, s, Me), 6.98 (1H, d, J 3 Hz, H-4, Th), 7.41 (1H, d, J 16.4 Hz, Het-HC=), 7.45-7.50 (3H, m, m,p-H),
7.64 (1H,d, J 3.4 Hz, H-3, Th), 7.84-7.87 (2H, m, o-H), 7.91 (1H, d, J 16.4 Hz, Ph-HC=). 13C NMR (101 MHz,
DMSO-d6): δC 15.6 (Me), 110.5 (Het-CH=), 125.5 (Th, C-5), 127.5 (p-C), 128.9 (m-C), 129.5 (o-C), 130.5 (Th, C-3),
131.1 (Th, C-4), 134.7 (i-C), 143.4 (Ph-CH=), 145.0 (Th, C-2), 164.5 (C-3), 175.6 (C-5). HRMS (ESI), m/z: calcd for
C15H13N2OS [M+H]+ 269.0743, found 269.0748.
2-{5-[(E)-2-Phenylethenyl]-1,2,4-oxadiazol-3-yl}pyridine (4n). Yield 74% (276 mg), white powder, mp 114-116
°С. IR, ν, cm–1: 980 (tr-СН=СН), 1071 (С–O), 1572 (C=N), 1644 (СH=СH). 1Н NMR(400 MHz, DMSO-d6): δH 7.46 -
7.50 (4H, m, m,p-H, Ph, Het-CH=), 7.63 (1H, ddd, J 7.6, 4.9, 1.2 Hz, H-5, Py), 7.86-7.88 (2H, m, o-H, Ph), 7.99
(1H, d, J 16.5 Hz, Ph-CH=), 8.05 (1H, td, J 7.7, 1.7 Hz, H-4, Py), 8.13 (1H, d, J 7.9 Hz, H-3, Py), 8.78 (1H, d, J 4.5
Hz, H-6, Py). 13C NMR (101 MHz, DMSO-d6): δC 110.7 (Het-CH=), 123.8 (Py, C-3), 126.6 (Py, C-5), 128.9 (o-C),
129.5 (m-C), 131.3 (p-C), 134.7 (i-C, Ph), 138.2 (Ph-CH=), 143.6 (Py, C-4), 146.3 (Py, C-2), 150.8 (Py, C-6), 168.6
(С-3), 176.2 (С-5). HRMS (ESI), m/z: calcd for C15H12N3O [M+H]+ 250.0974, found 250.0979.
3-Phenyl-5-(4-vinylphenyl)-1,2,4-oxadiazole (4o). Yield 88% (327 g), white powder, mp 75-77 °С. IR, ν, cm–1:
991 (СН=СН2), 1276 (С–O), 1594 (C=N), 1627 (СH=СH). 1Н NMR (400 MHz, DMSO-d6): δH 5.47 (1Н, d, J 10.9 Hz,
cis-CH=CH2), 6.05 (1Н, d, J 17.5 Hz, tr- CH=CH2), 6.86 (1Н, dd, J 17.5, 10.9 Hz, СН=CH2), 7.60 (3Н, m, m,p-H, Ph),
7.74 (2Н, d, J 7.9 Hz, Ar), 8.08-8.15 (4Н, m, o-H, Ph, Ar). 13C NMR (101 MHz, DMSO-d6): δC 118.1 (=CH2), 122.9
(i-C), 126.7 (p-C), 127.6 (o-C), 128.7 (m-C), 129.7 (m-C), 132.1 (i-C), 136.1 (-CH=), 142.2 (p-C), 168.7 (C-3), 175.6
(C-5). HRMS (ESI), m/z: calcd for C16H13N2O [M+H]+ 249.1022, found 249.1018.
3-(4-Chlorophenyl)-5-(4-ethenylphenyl)-1,2,4-oxadiazole (4p). Yield 85% (360 mg), white powder, mp 110-
112 °С. IR, ν,cm–1: 992 (СН=СН2), 1278 (С–O), 1589 (C=N), 1629 (СH=СH). 1Н NMR (400 MHz, DMSO-d6): δH 5.46
(1Н, d, J 10.9 Hz, cis-CH=CH2), 6.00 (1Н, d, J 17.5 Hz, tr-CH=CH2), 6.86 (1Н, dd, J 17.5, 10.9 Hz, СН=CH2), 7.58-
13
7.72 (4Н, m), 8.01-8.14 (4Н, m). C NMR (101 MHz, DMSO-d6): δC 117.9 (=CH2), 126.2 (i-C), 127.2 (p-C), 127.5
(o-C), 128.7 (m-C), 131.5 (m-C), 131.8 (i-C), 134.5 (-CH=), 136.2 (p-C), 142.5 (p-C), 167.8 (C-3), 176.0 (C-5).
HRMS (ESI), m/z: calcd for C16H12ClN2O [M+H]+ 283.0633, found 283.0622.
Antimicrobial assay
Overnight cultures were grown at 37 °C in Lysogeny broth (LB) and diluted to obtain an opacity equivalent to
0.5 on the McFarland scale. The compounds are weighed and dissolved in DMSO to give concentrations equal
to 21.4 µmol/mL. The pefloxacin and fluconazole were used as to antimicrobial drug standards. The
concentration of 2.14 µmol/mL was used as the starting one, providing a final concentration equal to 0.03
µmol/mL. The tubes were incubated for 12 h at 37 °C. Growth inhibition detection was considered as positive
results. It was verified that DMSO as completely inactive against the tested microorganisms in the less than 0.5
% concentrations. A series of tubes is prepared by mixing one part of each dilution of the compound with
some parts of the LB, previously inoculated and incubated for 24 h at 37 °C. All experiments were carried out
in triplicate. Minimum inhibitory concentration (MIC) is the lowest concentration of an antimicrobial agent
which will inhibit the visible growth of a micro-organism after overnight incubation.
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Acknowledgements
We thank Saint Petersburg State University for financial support (grant 12.37.214.2016). The antimicrobial
evaluation of synthesized 1,2,4-oxadiazoles was financially supported by the Russian Foundation for Basic
Research (RFBR) grant 18-33-01108.
We gratefully acknowledge Research Centre for Magnetic Resonance and Center for Chemical Analysis and
Materials Research of Saint Petersburg State University for NMR and HR-Mass spectra of novel compounds.
The authors thank Dr. Alexey Fedorov (ETH Zurich) for his help in the preparation of this manuscript.
Supplementary Material
Supplementary material, including physical constants and spectral data for known compounds (4a, 4c, 4e, 4f-
h), and copies of 1H and 13C NMR spectra for new compounds 4b, 4d, 4i-p can be accessed using the link
"Supplementary Material" in the journal issue contents page.
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