Electrophilic activation of nitroalkanes in efficient synthesis of 1,3,4-oxadiazoles

Article abstract of DOI:10.1039/c9ra00976k

A novel methodology for general and chemoselective preparation of non-symmetric 1,3,4-oxadiazoles is developed. This unusual reaction proceeds via polyphosphoric acid-assisted activation of nitroalkanes towards nucleophilic attack with acylhydrazides.

Full text of DOI:10.1039/c9ra00976k

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Electrophilic activation of nitroalkanes in efficient
synthesis of 1,3,4-oxadiazoles†
Cite this: RSC Adv., 2019, 9, 6636
a
a
a
*
Alexander V. Aksenov,
Vladislav Khamraev,
Nicolai A. Aksenov,
Nikita K. Kirilov,a Dmitriy A. Domenyuk,b Vladimir A. Zelenskyb
ac
*
and Michael Rubin
Received 5th February 2019
Accepted 12th February 2019
A novel methodology for general and chemoselective preparation of non-symmetric 1,3,4-oxadiazoles is
developed. This unusual reaction proceeds via polyphosphoric acid-assisted activation of nitroalkanes
towards nucleophilic attack with acylhydrazides.
DOI: 10.1039/c9ra00976k
rsc.li/rsc-advances
most of which are dealing with the moderation of the reactivity
of the acylating reagent.6 In addition, different schemes
involving cyclo-condensations of N0-alkylidene acylhy-
drazides,7 or re-cyclizations of tetrazoles,8 were also suggested.
Herein we wish to report a new preparative method for selec-
tive assembly of non-symmetrically substituted 1,3,4-oxadia-
zoles employing nitroalkanes electrophilicity activated in the
presence of polyphosphoric acid that serves as an acylating
agent equivalent.
Introduction
Bioisosteric to carboxylate and carboxamide functionalities,
1,3,4-oxadiazoles are oen considered among other privileged
heterocyclic scaffolds for drug discovery.1 Molecules possess-
ing these key structural fragments have demonstrated a wide
variety of important biological properties, including antibac-
terial, antimycobacterial, antifungal, insecticidal, herbicidal,
anti-inammatory, analgesic, anticonvulsant and anticancer
activities.2 Several medicinal agents featuring this heterocyclic
ring have been marketed, including anti-HIV drug Raltegravir,
antihypertensive Nesapidil, and anti-cancer agent Zibotentan
(Fig. 1). This heterocyclic building block was also used for the
construction of chiral catalysts3 and metal-selective chemo-
sensors.4 A symmetrically substituted version of this system (5)
can be easily obtained by cyclo-condensation of hydrazine
hydrate with a variety of carbonyl compounds.5 Assembly of
1,3,4-oxazoles 4 with two different substituents is much more
challenging, as it involves the selective reaction of hydrazine
with two different carbonyl compounds, or their synthetic
equivalents, to obtain non-symmetric N,N0-diacylhydrazide
precursor 2 (Scheme 1). Such processes, especially when
carried out in one-pot fashion, can be signicantly compli-
cated by side reactions involving trans-acylation of N,N0-diac-
ylhydrazide intermediates with excess of the second carbonyl
compound and leading to the formation of a mixture of non-
symmetric (4) and symmetric (5) products. A variety of
methods were suggested in an attempt to address this issue,
Results and discussion
For several years our group had a great interest in the devel-
opment of novel acid-mediated cascade transformations of
nitroalkenes and nitroalkanes targeting material science and
medicinal chemistry applications. It was demonstrated that
aDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation. E-mail: alexaks05@rambler.ru
bDepartment of General Practice Dentistry and Child Dentistry, Stavropol State
Medical University, 310 Mira Street, Stavropol 355017, Russian Federation
cDepartment of Chemistry, University of Kansas, 1567 Irving Hill Road, Lawrence, KS
66045-7582, USA. E-mail: mrubin@ku.edu; Tel: +1-785-864-5071
† Electronic supplementary information (ESI) available. CCDC 1875720, 1875721
and 1875723. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c9ra00976k
Fig. 1 1,3,4-Oxazoles in drug discovery and medicinal chemistry.
6636 | RSC Adv., 2019, 9, 6636–6642
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intramolecular 5-exo-trig cyclization involving the carbonyl
group of the hydrazide function and providing 4,5-dihydro-
1,3,4-oxadiazol-3-ium ion 15. The latter aer deprotonation
is expected to form 2,3-dihydro-1,3,4-oxadiazole 16, which
aer the elimination of O-phosphorylated hydroxylamine
would provide desired 1,3,4-oxadizole 4 (Scheme 2).
To test this idea, a mixture benzohydrazide (1a, R1 ¼ Ph) and
nitroethane (6a, R2 ¼ Me, 2.00 equiv.) was stirred in poly-
phosphoric acid (86% P2O5) at 70 ꢀC (Table 1, entry 1). However,
Scheme 1
ꢀ
even aer 90 min no reaction was observed. At 90 C the reac-
tion proceeded slowly and aer 30 min the conversion reached
14%, however the main product of the reaction was 2,5-
diphenyl-1,3,4-oxadiazole (5a, R2 ¼ Ph). At 110 ꢀC (boiling point
of nitroethane) the process proceeded to completion affording
mixtures of 10% of non-symmetric product 4aa and 55%
symmetric oxadiazole 5a (entry 3). The rest of the starting
material polymerized forming highly polar resins. Employment
of nitroethane (6a) in excess (3.00 equiv.) did not notably
improve the reaction outcome (entries 4 and 5). Evidently, the
symmetric product (5a) was formed via acid-mediated trans-
acylation of 1a to produce intermediate symmetric N,N0-diac-
ylhydrazide 3a (R2 ¼ Ph). In order to suppress this undesired
process, we decided to add starting hydrazide 1a in small
portions over an extended period of time. This resulted in only
marginal improvement, however, in the reactions carried out in
the presence of stoichiometric amount of nitroethane (entry 6).
Gradual increase of the concentration of nitroethane (entries 7–
10) resulted in both the conversion and chemoselectivity of the
process to achieve exclusive formation of product 5a at 99%
yield (entry 10). We also tested the possibility of employing
Eaton's reagent (P2O5 in MeSO3H) as a mixture that is oen
used as an alternative to PPA in synthesis, but in this medium
hydrazide 6a underwent complete hydrolysis to afford benzoic
acid as the only detectible product of the reaction (entries 11
and 12).
nitroalkanes 6 dissolved in polyphosphoric acid (PPA) trans-
form into phosphorylated nitronate 7 showing strong elec-
trophilic properties. This unusual species can be used to
design one-pot multi-step transformations involving various
carbon-based nucleophiles.9 The utilization of nucleophilic
amines was also demonstrated.10 Mechanistically, the latter
process is related to the classical Nef reaction,11 employing
aniline species 8 instead of water. This reaction provides
imidinium ion 9, that can be further employed as a convenient
building block for the synthesis of heterocyclic compounds:
oxazoles 10, imidazoles 11, and diazines 12–13 (Scheme 2).10
We wondered about the possibility of employing acylhy-
drazides 1 as nucleophilic components en route to the 1,3,4-
oxazoles scaffolds. Indeed, such a nucleophilic attack to
nitronate species 7 would afford (2-acylhydrazineyl)alka-
niminium species 14,12 that should be well suited for an
With the optimized reaction conditions in hand we
carried out the reaction between 1a and 6a in preparative
Table 1 Optimization of reaction conditions for cyclocondensation of
1a and 6a to produce oxadiazoles 4aa and 5a
6a (equiv.)
Medium
86% PPA
T, ꢀC (time)
4aa : 5aa
1
2
3
4
5
6
7
8
1.00
1.00
1.00
3.00
3.00
1.00
2.00
3.00
5.00
7.00
3.00
3.00
70 (1.5 h)b
90 (0.5 h)b
110 (0.5 h)b
90 (0.5 h)b
110 (1 h)b
110 (1 h)c
110 (1 h)c
110 (1 h)c
110 (1.5 h)c
110 (1.5 h)c
110 (1 h)
0 : 0
0 : 14
10 : 55
0 : 17
31 : 61
12 : 38
63 : 25
64 : 15
94 : 6
99 : 0
0 : 0d
9
10
11
12
Eaton's reagent 1 : 7
Eaton's reagent 1 : 10
110 (1 h)
0 : 0d
a
NMR yields of compounds 4a and 5a are shown. b Benzohydrazide was
added in a single portion. c Benzohydrazide was slowly added by small
portions. Complete hydrolysis of benzohydrazide was observed,
d
affording benzoic acid as sole product.
Scheme 2
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Scheme 3
scale (1.00 mmol). We were pleased to nd, that oxadiazole 100 ꢀC (boiling point of nitromethane). Gratifyingly, these
4aa was obtained in this reaction as sole product and isolated reactions proceeded smoothly affording the corresponding 2-
in high yield (Scheme 3, entry 1). Hydrazides 1b–g, derived aryl-1,3,4-oxadiazoles 4ab–4gb in high yields (Scheme 3, entries
from other aryl- and hetarylcarboxylic acids, also reacted with 8–14). Along the same lines, we tested the possibility of
nitroethane (6a) smoothly, affording the corresponding employing (2-nitroethyl)benzenes (6c–d) as electrophilic
heterocyclic products (entries 2–7). Remarkably, non- components in the featured transformation. These reactions
protected phenols 1e and 1f also reacted uneventfully, were more sluggish, probably due to excessive steric hindrance
which showcases the dual role of polyphosphoric acid as in the phosphorylated nitronate intermediates 7. It was found,
a versatile reaction medium with acidic properties and as however, that the cyclo-condensation could be pushed to
ꢀ
a reagent for the reversible installation of temporary pro- complete conversion at 140 C to afford the corresponding 5-
tecting phosphatyl groups.
benzyloxadiazoles 4ac, 4ad, and 4cd albeit in somewhat lower
Thorough analysis of literature revealed that synthetic access yields (entries 15–17).
to monosubstituted oxadiazoles is especially challenging, since
Another major challenge in chemistry of 1,3,4-oxadiazoles is
preparation of non-symmetric bis-hydrazides 2 required for this associated with incorporation of ester substituents at C-2 of this
cyclo-condensation is severely complicated by relatively high heterocyclic scaffold.15 To address this issue we attempted the
strength formic acid and elevated electrophilicity of for- reaction of various benzohydrazides (1a,b,e) with ethyl 2-nitro-
mohydrazide derivatives.13 This problem can be typically cir- acetate. We were pleased to discover that this reaction also
cumvented by usage of orthoformates as acylating agents.14 We proceeded smoothly under standard reaction conditions
ꢀ
felt, however, that in our featured methodology, there should (temperature was raised to 130 C to ensure complete conver-
not be a dramatic difference between reactivity of nitroethane sion) affording the corresponding 1,3,4-oxadiazole-2-
(6a) and nitromethane (6b). This would allow for the develop- carboxylates as the sole isolable product (Scheme 3, entries
ment of a very general synthetic protocol to access 1,3,4-oxa- 18–20).
diazoles with different substitution patterns. To test this
The formation and structural identity of compounds 5a, 4ga,
possibility, we carried out reactions with a series of benzohy- and 4ca was unambiguously conrmed by a single crystal X-ray
drazides (1a–g) in the presence of excess nitromethane (6b) at crystallography (Fig. 2).
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asks open to the atmosphere, employing overhead stirring.
The reaction progress and purity of isolated compounds were
controlled by TLC on Silufol UV-254 plates, with EtOAc as
eluent. PPA was obtained by dissolving of P2O5 in 85% ortho-
phosphoric acid according to the published protocol.16 All
reagents and solvents were purchased from commercial
vendors and used as received. Physical and spectral properties
of compound 5a were identical to those reported in literature.17
2-Methyl-5-phenyl-1,3,4-oxadiazole (4aa V210). Typical
procedure. A 10 mL Erlenmeyer ask equipped with magnetic
bar and reux condenser was charged with polyphosphoric acid
(86% P2O5, 1.5 g) and nitroethane (6a) (500 mL, 525 mg, 7.00
mmol) and heated while stirring at 105–115 ꢀC. Benzohydrazide
(1a) (136 mg, 1.00 mmol) was added slowly in small portions
over 1 h, and the mixture was heated for an additional 30 min,
when TLC analysis showed the completion of the reaction. The
mixture was diluted with water (5 mL), neutralized with 25%
aqueous ammonia (4.5–5.0 mL is typically required), and
extracted with EtOAc (4 ꢁ 5 mL). Combined organic phases
were concentrated and the crude product was puried by
preparative column chromatography eluting with EtOAc/
petroleum ether mixture 1 : 1 to obtain the titled compound
as a colorless solid, mp 63–65 ꢀC (EtOAc), Rf 0.39 (EtOAc/
petroleum ether, 1 : 1). Yield 146 mg (0.91 mmol, 91%). 1H
NMR (400 MHz, CDCl3) d 8.02 (d, J ¼ 7.8 Hz, 2H), 7.55–7.46 (m,
3H), 2.61 (s, 3H); 13C NMR (101 MHz, CDCl3) d 165.0, 163.8,
131.7, 129.1, 126.8, 124.0, 11.3; IR (KBr, lm, cmꢂ1): 3060, 2943,
1582, 1556, 1487, 1450, 1252, 1095, 1073, 1021, 959; HRMS (ESI
TOF) calculated for C9H8N2NaO (M + Na)+ 183.0529, found
183.0531 (1.3 ppm).
Fig. 2 ORTEP drawings of 5a (top, CCDC #1875720), 4ga (middle,
CCDC #1875721), and 4ca (bottom, CCDC #1875723) showing atom
numbering schemes and 50% probability ellipsoids.
2-(2-Bromophenyl)-5-methyl-1,3,4-oxadiazole (4ba V226).
This material was obtained from 2-bromobenzohydrazide (1b)
(215 mg, 1.00 mmol) and nitroethane (6a) (500 mL, 525 mg, 7.00
ꢀ
mmol). The reaction was carried at 105–115 C, and the titled
Conclusion
compound was isolated as a yellowish oil, Rf 0.37 (EtOAc/
petroleum ether, 1 : 3). Yield 199 mg (83%). 1H NMR (400
MHz, CDCl3) d 7.89 (d, J ¼ 7.7 Hz, 1H), 7.74 (d, J ¼ 8.0 Hz, 1H),
In conclusion, the novel one-pot multistep reaction sequence
involving
cyclo-condensation
of
acylhydrazides
with
7.44 (t, J ¼ 7.6 Hz, 1H), 7.38 (t, J ¼ 7.7 Hz, 1H), 2.64 (s, 3H); 13
C
electrophilicity-activated nitroalkanes was investigated. Careful
optimization of the reaction conditions resulted in excellent
chemo-selectivity of this newly developed synthetic protocol
towards monosubstituted and non-symmetrically disubstituted
1,3,4-oxadiazoles. High yields of the resulting heterocyclic
products and great functional group compatibility of this
synthetic methodology was demonstrated.
NMR (101 MHz, CDCl3) d 164.3, 164.0, 134.6, 132.5, 131.7, 127.7,
125.5, 121.7, 11.3; IR (KBr, lm, cmꢂ1) 3071, 2932, 1586, 1435,
1347, 1241, 1098, 1021, 959; HRMS (ESI TOF) calculated for
C9H7BrN2NaO (M + Na)+ 260.9634, found 260.9630 (1.7 ppm).
2-Methyl-5-(pyridin-3-yl)-1,3,4-oxadiazole (4ca V229). This
material was obtained from nicotinohydrazide (1c) (137 mg,
1.00 mmol) and nitroethane (6a) (500 mL, 525 mg, 7.00 mmol).
The reaction was carried out at 105–115 ꢀC, and the titled
compound was isolated as a colorless solid, precipitated aer
aqueous work up and basication. No chromatographic puri-
cation was required. Mp 114–116 ꢀC (EtOAc), Rf 0.43 (EtOAc/
Experimental part
General information
1H and 13C NMR spectra were recorded on a Bruker Avance-III EtOH, 4 : 1). Yield 159 mg (0.99 mmol, 99%). 1H NMR (400
spectrometer (400 or 100 MHz, respectively) equipped with MHz, CDCl3) d 9.25 (s, 1H), 8.77 (d, J ¼ 4.7 Hz, 1H), 8.38 (d, J ¼
a BBO probe in CDCl3 or DMSO-d6, using TMS as an internal 8.0 Hz, 1H), 7.50 (dd, J ¼ 7.9, 5.0 Hz, 1H), 2.65 (s, 3H); 13C NMR
standard. High-resolution mass spectra were registered with (101 MHz, CDCl3) d 164.5, 162.7, 151.8, 147.2, 134.7, 124.2,
a Bruker Maxis spectrometer (electrospray ionization, in MeCN 120.9, 11.9; IR (KBr, lm, cmꢂ1) 3082, 3049, 2932, 1593, 1575,
solution, using HCO2Na–HCO2H for calibration). Melting 1549, 1468, 1432, 1351, 1259, 1087, 1010, 988, 959; HRMS (ESI
points were measured with a Stuart smp30 apparatus. All TOF) calculated for C8H7N3NaO (M + Na)+ 184.0481, found
reactions were performed in oven-dried 5 mL round-bottomed 183.0482 (0.2 ppm).
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was carried out at 95–105 ꢀC, and the titled compound was
isolated as a colorless oil, Rf 0.24 (EtOAc/petroleum ether, 1 : 3).
Yield 119 mg (0.81 mmol, 81%). 1H NMR (400 MHz, CDCl3)
d 8.48 (s, 1H), 8.11–8.05 (m, 2H), 7.57–7.49 (m, 3H); 13C NMR
(101 MHz, CDCl3) d 164.9, 152.8, 132.2, 129.3, 127.2, 123.6; IR
(KBr, lm, cmꢂ1) 3064, 1578, 1556, 1487, 1450, 1355, 1248, 1091,
1076, 1025, 959, 930; HRMS (ESI TOF) calculated for
C8H6N2NaO (M + Na)+ 169.0372, found 169.0373 (0.3 ppm).
2-(2-Bromophenyl)-1,3,4-oxadiazole (4bb V232). This mate-
rial was obtained from 2-bromobenzohydrazide (1b) (215 mg,
1.00 mmol) and nitromethane (6b) (581 mL, 610 mg, 10.0 mmol).
The reaction was carried out at 95–105 ꢀC, and the titled
compound was isolated as a yellow oil, Rf 0.28 (EtOAc/petroleum
ether, 1 : 3). Yield 162 mg (0.72 mmol, 72%). 1H NMR (400 MHz,
CDCl3) d 8.57 (s, 1H), 7.94 (d, J ¼ 7.7 Hz, 1H), 7.77 (d, J ¼ 7.9 Hz,
1H), 7.48 (t, J ¼ 7.5 Hz, 1H), 7.41 (t, J ¼ 7.7 Hz, 1H); 13C NMR
(101 MHz, CDCl3) d 163.9, 153.2, 134.7, 132.9, 131.9, 127.8,
125.1, 121.9; IR (KBr, lm, cmꢂ1) 3119, 3002, 1597, 1575, 1516,
1457, 1432, 1234, 1109, 1084, 1025, 952; HRMS (ESI TOF)
calculated for C8H5BrN2NaO (M + Na)+ 246.9477, found
246.9479 (0.6 ppm).
2-(Pyridin-3-yl)-1,3,4-oxadiazole (4cb V230). This material
was obtained from nicotinohydrazide (1c) (137 mg, 1.00 mmol)
and nitromethane (6b) (581 mL, 610 mg, 10.0 mmol). The reac-
tion was carried out at 95–105 ꢀC, and the titled compound was
isolated aer extraction with dichloromethane (4 ꢁ 5 mL) as
a colorless solid, mp 72–73 ꢀC (EtOAc); Rf 0.51 (EtOAc/EtOH,
4 : 1). Yield 116 mg (0.79 mmol, 79%). 1H NMR (400 MHz,
CDCl3) d 9.31 (s, 1H), 8.84–8.76 (m, 1H), 8.55 (s, 1H), 8.39 (d, J ¼
8.0 Hz, 1H), 7.49 (dd, J ¼ 8.0, 4.9 Hz, 1H); 13C NMR (101 MHz,
CDCl3) d 162.9, 153.2, 152.9, 148.2, 134.6, 124.0, 120.2, 77.2; IR
(KBr, lm, cmꢂ1) 3332, 3071, 2998, 1608, 1586, 1556, 1512, 1468,
1432, 1267, 1131, 1102, 1073, 1021, 952, 897; HRMS (ESI TOF)
calculated for C7H5N3NaO (M + Na)+ 170.0325, found 170.0330
(3.1 ppm).
2-Methyl-5-(4-nitrophenyl)-1,3,4-oxadiazole (4da V233). This
material was obtained from 4-nitrobenzohydrazide (1d)
(181 mg, 1.00 mmol) and nitroethane (6a) (500 mL, 525 mg, 7.00
mmol). The reaction was carried out at 105–115 ꢀC, and the
titled compound was isolated as a yellow solid, mp 168–170 ꢀC
(EtOAc), Rf 0.27 (EtOAc/petroleum ether, 1 : 1). Yield 191 mg
(0.93 mmol, 93%). 1H NMR (400 MHz, CDCl3) d 8.37 (d, J ¼
8.7 Hz, 2H), 8.22 (d, J ¼ 8.6 Hz, 2H), 2.67 (s, 3H); 13C NMR (101
MHz, CDCl3) d 164.9, 163.4, 149.6, 129.6, 127.8, 124.5, 11.3; IR
(KBr, lm, cmꢂ1) 3108, 3071, 3016, 2932, 1578, 1553, 1520, 1351,
1333, 1311, 1292, 1234, 1087, 1032, 867; HRMS (ESI TOF)
calculated for C9H7N3NaO3 (M + Na)+ 228.0380, found 228.0378
(0.8 ppm).
2-(5-Methyl-1,3,4-oxadiazol-2-yl)phenol (4ea V235). This
material was obtained from 2-hydroxybenzohydrazide (1e)
(152 mg, 1.00 mmol) and nitroethane (6a) (500 mL, 525 mg, 7.00
mmol). The reaction was carried out at 105–115 ꢀC, and the
titled compound was isolated as a light-brown solid, mp 73–
75 ꢀC (acetone/EtOAc), Rf 0.38 (EtOAc/petroleum ether, 1 : 3).
Yield 143 mg (0.87 mmol, 87%). 1H NMR (400 MHz, CDCl3)
d 10.12 (br, s, 1H), 7.73 (dd, J ¼ 7.9, 1.5 Hz, 1H), 7.47–7.38 (m,
1H), 7.12 (d, J ¼ 8.4 Hz, 1H), 7.04–6.94 (m, 1H), 2.65 (s, 3H); 13
C
NMR (101 MHz, CDCl3) d 164.7, 162.6, 157.6, 133.6, 126.5, 120.0,
117.7, 108.3, 11.2; IR (KBr, lm, cmꢂ1) 3189, 3071, 2976, 2943,
1629, 1593, 1549, 1490, 1439, 1410, 1355, 1300, 1241, 1080,
1040, 963; HRMS (ESI TOF) calculated for C9H8N2NaO2 (M +
Na)+ 199.0478, found 199.0476, (1.0 ppm).
4-(5-Methyl-1,3,4-oxadiazol-2-yl)phenol (4fa V242). This
material was obtained from 4-hydroxybenzohydrazide (1f)
(152 mg, 1.00 mmol) and nitroethane (6a) (500 mL, 525 mg, 7.00
mmol). The reaction was carried out at 105–115 ꢀC, and the
titled compound was isolated as a light-brown solid, mp 236–
ꢀ
238 C (acetone/EtOAc); Rf 0.30 (EtOAc/petroleum ether, 2 : 1).
1
Yield 146 mg (0.83 mmol, 83%). H NMR (400 MHz, DMSO-d6)
d 10.28 (s, 1H), 7.79 (d, J ¼ 8.7 Hz, 2H), 6.93 (d, J ¼ 8.7 Hz, 2H),
2.53 (s, 3H); 13C NMR (101 MHz, DMSO-d6) d 164.1, 163.1, 160.6,
128.3, 116.2, 114.4, 10.6. IR (KBr, lm, cmꢂ1) 3156, 3020, 2947,
1611, 1589, 1494, 1377, 1289, 1234, 1164, 1120, 1073, 933, 853;
HRMS (ESI TOF) calculated for C9H8N2NaO2 (M + Na)+ 199.0478,
found 199.0482 (1.9 ppm).
2-(4-Nitrophenyl)-1,3,4-oxadiazole (4db V245). This material
was obtained from 4-nitrobenzohydrazide (1d) (181 mg, 1.00
mmol) and nitromethane (6b) (581 mL, 610 mg, 10.0 mmol). The
reaction was carried out at 95–105 ꢀC, and the titled compound
ꢀ
was isolated as a yellow solid, mp 152–153 C (EtOAc), Rf 0.32
(EtOAc/petroleum ether, 1 : 2). Yield 165 mg (0.86 mmol, 86%).
1H NMR (400 MHz, CDCl3) d 8.58 (s, 1H), 8.40 (d, J ¼ 8.9 Hz, 2H),
8.30 (d, J ¼ 8.9 Hz, 2H); 13C NMR (101 MHz, CDCl3) d 163.3,
153.6, 149.9, 129.1, 128.3, 124.6; IR (KBr, lm, cmꢂ1) 3163, 3108,
3075, 3009, 1611, 1560, 1520, 1333, 1311, 1296, 1113, 1065, 948,
853; HRMS (ESI TOF) calculated for C8H5N3NaO3 (M + Na)+
214.0223, found 214.0225 (1.1 ppm).
2-(1,3,4-Oxadiazol-2-yl)phenol (4eb V247). This material was
obtained from 2-hydroxybenzohydrazide (1e) (152 mg, 1.00
mmol) and nitromethane (6b) (581 mL, 610 mg, 10.0 mmol). The
reaction was carried out at 95–105 ꢀC, and the titled compound
was isolated as a colorless solid, mp 84–86 ꢀC (acetone), Rf 0.35
(EtOAc/petroleum ether, 1 : 3). Yield 131 mg (0.81 mmol, 81%);
1H NMR (400 MHz, CDCl3) d 10.06 (s, 1H), 8.47 (s, 1H), 7.79 (d, J
¼ 7.8 Hz, 1H), 7.47 (t, J ¼ 7.7 Hz, 1H), 7.14 (d, J ¼ 8.4 Hz, 1H),
7.02 (t, J ¼ 7.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) d 164.5,
157.8, 151.5, 134.2, 126.9, 120.2, 117.8, 107.9; IR (KBr,
2-(2,4-Dichlorophenyl)-5-methyl-1,3,4-oxadiazole (4ga V240).
This material was obtained from 2,4-dichlorobenzohydrazide
(1g) (205 mg, 1.00 mmol) and nitroethane (6a) (500 mL, 525 mg,
7.00 mmol). The reaction was carried out at 105–115 ꢀC, and the
titled compound was isolated as a colorless solid, mp 92–102 ꢀC
(EtOAc), Rf 0.50 (EtOAc/petroleum ether, 1 : 1). Yield 199 mg
(0.87 mmol, 87%). 1H NMR (400 MHz, CDCl3) d 7.92 (d, J ¼
8.5 Hz, 1H), 7.56 (d, J ¼ 1.9 Hz, 1H), 7.39 (dd, J ¼ 8.5, 1.9 Hz,
1H), 2.64 (s, 3H); 13C NMR (101 MHz, CDCl3) d 164.4, 162.7,
138.1, 133.9, 131.9, 131.3, 127.7, 121.9, 11.3; IR (KBr, lm, cmꢂ1
)
3104, 3086, 3009, 2936, 1589, 1564, 1454, 1417, 1270, 1241,
1106, 1018, 963, 879; HRMS (ESI TOF) calculated for C9H6Cl2-
N2NaO (M + Na)+ 250.9749, found 250.9747 (0.8 ppm).
2-Phenyl-1,3,4-oxadiazole (4ab V216). This material was ob-
tained from benzohydrazide (1a) (136 mg, 1.00 mmol) and
nitromethane (6b) (581 mL, 610 mg, 10.0 mmol). The reaction
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lm, cmꢂ1) 3222, 3148, 3068, 1769, 1728, 1626, 1586, 1549,
1490, 1406, 1303, 1256, 1157, 1095, 1058, 952; HRMS (ESI TOF)
calculated for C8H6N2NaO2 (M + Na)+ 185.0321, found 185.0320
(1.0 ppm).
2-(4-Chlorobenzyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole
(4cd
V254). This material was obtained from nicotinohydrazide (1c)
(137 mg, 1.00 mmol) and 1-chloro-4-(2-nitroethyl)benzene (6c)
(220 mL, 278 mg, 1.50 mmol). The reaction was carried out at
130–135 ꢀC, and the titled compound was isolated as a colorless
4-(1,3,4-Oxadiazol-2-yl)phenol (4 V260). This material was
obtained from 4-hydroxybenzohydrazide (1f) (152 mg, 1.00
mmol) and nitromethane (6b) (581 mL, 610 mg, 10.0 mmol). The
reaction was carried out at 95–105 ꢀC, and the titled compound
ꢀ
solid, mp 112–114 C (EtOAc), Rf 0.34 (EtOAc/petroleum ether,
1 : 3). Yield 146 mg (0.54 mmol, 54%). 1H NMR (400 MHz,
CDCl3) d 9.22 (s, 1H), 8.77 (d, J ¼ 4.3 Hz, 1H), 8.35 (d, J ¼ 7.9 Hz,
1H), 7.49 (dd, J ¼ 7.8, 4.9 Hz, 1H), 7.33 (q, J ¼ 8.5 Hz, 4H), 4.28
(s, 2H); 13C NMR (101 MHz, CDCl3) d 165.7, 163.1, 151.8, 147.2,
134.9, 134.0, 132.0, 130.4, 129.4, 124.2, 120.7, 31.4; IR (KBr,
lm, cmꢂ1) 3090, 3064, 2958, 2925, 2855, 1567, 1490, 1413,
ꢀ
was isolated as a colorless solid, mp 127–129 C (acetone), Rf
0.34 (EtOAc/petroleum ether, 1 : 1). Yield 130 mg (0.81 mmol,
1
81%). H NMR (400 MHz, CDCl3) d 10.33 (s, 1H), 9.23 (s, 1H),
7.85 (d, J ¼ 8.6 Hz, 2H), 6.95 (d, J ¼ 8.6 Hz, 2H); 13C NMR (101
MHz, CDCl3) d 163.8, 160.9, 153.8, 128.7, 116.2, 114.0; IR (KBr,
lm, cmꢂ1) 3147, 3027, 1615, 1597, 1498, 1384, 1285, 1245,
1179, 1128, 1065, 966, 941, 853; HRMS (ESI TOF) calculated for
C8H6N2NaO2 (M + Na)+: 185.0321, found 185.0326 (2.3 ppm).
2-(2,4-Dichlorophenyl)-1,3,4-oxadiazole (4gb V246). This
material was obtained from 2,4-dichlorobenzohydrazide (1g)
(205 mg, 1.00 mmol) and nitromethane (6b) (581 mL, 610 mg,
10.0 mmol). The reaction was carried out at 95–105 ꢀC, and the
titled compound was isolated as a colorless solid, mp 141–
151 ꢀC (EtOAc), Rf 0.41 (EtOAc/petroleum ether, 1 : 2). Yield
192 mg (0.89 mmol, 89%). 1H NMR (400 MHz, CDCl3) d 8.57 (s,
1H), 7.96 (d, J ¼ 8.5 Hz, 1H), 7.58 (d, J ¼ 1.9 Hz, 1H), 7.41 (dd, J ¼
8.5, 1.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) d 162.7, 153.2,
1256, 1186, 1084, 1007, 963, 853; HRMS calculated for C14H10
ClN3NaO (M + Na)+ 294.0405, found 293.0395, (3.2 ppm).
-
Ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (4ae V269).
This material was obtained from benzohydrazide (1a) (136 mg,
1.00 mmol) and ethyl 2-nitroacetate (6e) (165 mL, 200 mg, 1.50
mmol). The reaction was carried out at 120–130 ꢀC, and the
titled compound was isolated as a colorless oil, Rf 0.47 (EtOAc/
petroleum ether, 1 : 3). Yield 136 mg (0.64 mmol, 64%). 1H NMR
(400 MHz, CDCl3) d 8.20–8.14 (m, 2H), 7.63–7.58 (m, 1H), 7.57–
7.52 (m, 2H), 4.56 (q, J ¼ 7.1 Hz, 2H), 1.48 (t, J ¼ 7.1 Hz, 3H); 13
C
NMR (101 MHz, CDCl3) d 166.6, 156.6, 154.6, 133.0, 129.4, 127.8,
122.9, 63.7, 14.3; IR (KBr, lm, cmꢂ1) 3078, 2994, 2941, 1748,
1625, 1546, 1478, 1452, 1377, 1242, 1190, 1163, 1070, 1017, 841,
792, 713, 691; HRMS (ESI TOF) calculated for C11H10N2NaO3 (M
+ Na)+ 241.0584, found 241.0577 (2.8 ppm).
138.6, 134.2, 132.1, 131.4, 127.8, 121.4; IR (KBr, lm, cmꢂ1
)
3314, 3204, 3093, 3027, 1659, 1633, 1593, 1512, 1457, 1377,
1307, 1252, 1106, 1058, 959, 893, 864; HRMS (ESI TOF) calcu-
lated for C8H4Cl2N2NaO (M + Na)+ 236.9593, found 236.9588
(2.1 ppm).
Ethyl 5-(2-bromophenyl)-1,3,4-oxadiazole-2-carboxylate (4be
V273). This material was obtained from 2-bromobenzohydrazide
(1b) (215 mg, 1.00 mmol) and ethyl 2-nitroacetate (6e) (165 mL,
200 mg, 1.50 mmol). The reaction was carried out at 120–130 ꢀC,
and the titled compound was isolated as a colorless oil, Rf 0.30
(EtOAc/petroleum ether, 1 : 3). Yield 205 mg (0.69 mmol, 69%).
1H NMR (400 MHz, CDCl3) d 8.00 (dd, J ¼ 7.6, 1.8 Hz, 1H), 7.79
(dd, J ¼ 7.8, 1.3 Hz, 1H), 7.49 (td, J ¼ 7.5, 1.4 Hz, 1H), 7.44 (td, J ¼
7.7, 1.9 Hz, 1H), 4.56 (q, J ¼ 7.1 Hz, 2H), 1.48 (t, J ¼ 7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3) d 165.5, 157.0, 154.5, 134.9, 133.5,
132.2, 127.9, 124.4, 122.2, 63.8, 14.2; IR (KBr, lm, cmꢂ1) 2985,
1748, 1598, 1535, 1441, 1377, 1298, 1253, 1186, 1167, 1100, 1028,
841, 770, 732; HRMS (ESI TOF) calculated for C11H9BrN2NaO3 (M
+ Na)+ 318.9689, found 318.9692 (1.0 ppm).
2-Benzyl-5-phenyl-1,3,4-oxadiazole (4ac V251). This material
was obtained from benzohydrazide (1a) (136 mg, 1.00 mmol)
and (2-nitroethyl)benzene (6c) (202 mL, 226 mg, 1.50 mmol). The
reaction was carried out at 130–135 ꢀC, and the titled compound
ꢀ
was isolated as a colorless solid, mp 93–95 C (EtOAc), Rf 0.35
(EtOAc/petroleum ether, 1 : 3). Yield 139 mg (0.59 mmol, 59%).
1H NMR (400 MHz, CDCl3) d 8.04–7.97 (m, 2H), 7.52–7.45 (m,
3H), 7.36 (d, J ¼ 4.3 Hz, 3H), 7.31 (dd, J ¼ 8.6, 4.2 Hz, 1H), 4.29
(s, 2H); 13C NMR (101 MHz, CDCl3) d 165.4, 165.3, 134.0, 131.8,
129.12, 129.08, 129.0, 127.7, 127.0, 124.0, 32.1; IR (KBr,
lm, cmꢂ1) 3075, 2928, 2858, 1567, 1553, 1490, 1454, 1424,
1256, 1095, 1065, 1010, 959; HRMS (ESI TOF) calculated for
Ethyl
5-(2-hydroxyphenyl)-1,3,4-oxadiazole-2-carboxylate
C
15H12N2NaO (M + Na)+: 259.0842, found 259.0842 (0.0 ppm).
(4ee V274). This material was obtained from 2-hydrox-
ybenzohydrazide (1e) (152 mg, 1.00 mmol) and ethyl 2-nitro-
acetate (6e) (165 mL, 200 mg, 1.50 mmol). The reaction was
carried out at 120–130 ꢀC, and the titled compound was isolated
as a colorless oil, Rf 0.35 (EtOAc/petroleum ether, 1 : 3). Yield
164 mg (0.70 mmol, 70%). 1H NMR (400 MHz, CDCl3) d 9.92 (s,
1H), 7.87 (dd, J ¼ 7.9, 1.6 Hz, 1H), 7.53–7.46 (m, 1H), 7.14 (d, J ¼
8.0 Hz, 1H), 7.06–7.00 (m, 1H), 4.56 (q, J ¼ 7.1 Hz, 2H), 1.48 (t, J
¼ 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 166.2, 158.4, 155.1,
154.2, 135.1, 127.4, 120.4, 118.0, 107.2, 63.9, 14.2; IR (KBr,
lm, cmꢂ1) 3245, 2986, 1748, 1625, 1542, 1493, 1377, 1313,
1242, 1186, 1163, 1058, 1021, 852, 751, 710, 676; HRMS (ESI
TOF) calculated for C11H10N2NaO4 (M + Na)+ 257.0533, found
257.0532 (0.5 ppm).
2-(4-Chlorobenzyl)-5-phenyl-1,3,4-oxadiazole (4ad V253).
This material was obtained from benzohydrazide (1a) (136 mg,
1.00 mmol) and 1-chloro-4-(2-nitroethyl)benzene (6d) (220 mL,
278 mg, 1.50 mmol). The reaction was carried out at 130–135 ꢀC,
and the titled compound was isolated as a colorless solid, mp
107–109 ꢀC (EtOAc); Rf 0.24 (EtOAc/petroleum ether, 1 : 3). Yield
162 mg (0.60 mmol, 60%). 1H NMR (400 MHz, CDCl3) d 8.00 (dd,
J ¼ 8.0, 1.4 Hz, 2H), 7.53–7.45 (m, 3H), 7.32 (q, J ¼ 8.6 Hz, 4H),
4.25 (s, 2H); 13C NMR (101 MHz, CDCl3) d 165.4, 164.9, 133.7,
132.4, 131.9, 130.3, 129.3, 129.2, 127.0, 123.8, 31.4; IR (KBr,
lm, cmꢂ1) 3068, 2928, 2855, 1553, 1490, 1450, 1380, 1194,
1087, 1010, 961; HRMS (ESI TOF) calculated for C15H11ClN2NaO
(M + Na)+ 293.0452, found 293.0460 (2.7 ppm).
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(b) A. V. Aksenov, N. A. Aksenov, O. N. Nadein and
I. V. Aksenova, Synlett, 2010, 2628–2630.
Conflicts of interest
10 (a) N. A. Aksenov, A. V. Aksenov, O. N. Nadein, D. A. Aksenov,
A. N. Smirnov and M. Rubin, RSC Adv., 2015, 5, 71620–71626;
(b) A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, A. S. Bijieva,
I. V. Aksenova and M. Rubin, Org. Biomol. Chem., 2015, 13,
4289–4295; (c) A. V. Aksenov, N. A. Aksenov,
D. S. Ovcharov, D. A. Aksenov, G. Griaznov,
L. G. Voskressensky and M. Rubin, RSC Adv., 2016, 6,
82425–82431; (d) A. V. Aksenov, D. S. Ovcharov,
N. A. Aksenov, D. A. Aksenov, O. N. Nadein and M. Rubin,
RSC Adv., 2017, 7, 29927–29932; (e) A. V. Aksenov,
N. A. Aksenov, S. V. Scherbakov, A. N. Smirnov,
I. V. Aksenova, V. I. Goncharov and M. A. Rubin, Russ. J.
Org. Chem., 2017, 53, 1081–1084; (f) A. I. Konovalov, et al.,
Russ. J. Org. Chem., 2018, 54, 157–371.
11 For reviews, see: (a) R. Ballini and M. Petrini, Adv. Synth.
Catal., 2015, 357, 2371–2402; (b) R. Ballini and M. Petrini,
Tetrahedron, 2004, 60, 1017–1047.
12 Formation of species 14 was unambiguously conrmed by
high resolution ESI MS analysis of the reaction mixture.
See ESI (page S55†) for details.
13 (a) M.-F. Pouliot, L. Angers, J.-D. Hamel and J.-F. Paquin,
Org. Biomol. Chem., 2012, 10, 988–993; (b) Q. Gao, S. Liu,
X. Wu, J. Zhang and A. Wu, Org. Lett., 2015, 17, 2960–2963.
14 (a) N. Salvanna, G. C. Reddy, B. R. Rao and B. Das, RSC Adv.,
2013, 3, 20538–20544; (b) K. K. Gnanasekaran,
B. Nammalwar, M. Murie and R. A. Bunce, Tetrahedron
Lett., 2014, 55, 6776–6778; (c) T. Kawano, K. Hirano,
T. Satoh and M. Miura, J. Am. Chem. Soc., 2010, 132, 6900–
6901; (d) L.-H. Zou, J. Reball, J. Mottweiler and C. Bolm,
Chem. Commun., 2012, 48, 11307–11309.
There are no conicts to declare.
Acknowledgements
This work was nanced by the Russian Foundation for Basic
Research (grant #18-33-20021 mol_a_ved) grants from the
Ministry of Education and Science of the Russian Federation
#4.1196.2017/4.6 and #4.4589.2017/6.7.
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6642 | RSC Adv., 2019, 9, 6636–6642
This journal is © The Royal Society of Chemistry 2019