On-water, catalyst-free and room-temperature construction of 2-aryl-1,3,4-oxadiazole derivatives from 1,1-dichloro-2-nitroethene and hydrazides

Article abstract of DOI:10.1039/c5ra11213c

2-Aryl-1,3,4-oxadiazoles are important functional molecules in many research fields. A green synthetic method for preparation of 2-aryl-1,3,4-oxadiazoles was developed using hydrazides and highly reactive 1,1-dichloro-2-nitroethene. This eco-friendly protocol featured high yields, purification simplicity, water-based reaction medium, energy efficiency and no addition of catalysts.

Full text of DOI:10.1039/c5ra11213c

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On-water, Catalyst-Free and Room-temperature Construction of
2-Aryl-1,3,4-oxadiazole Derivatives from 1,1-Dichloro-2-nitroethene
and Hydrazides
Fengjuan Zhu, Minming Zou, Xusheng Shao* and Zhong Li
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of
Science and Technology, Shanghai, 200237, China
Phone: +86-21-64253967. Fax: +86-21-64252603. E-mail: shaoxusheng@ecust.edu.cn.
Table of contents entry
The image of Construction of 2-Aryl-1,3,4-oxadiazole Derivatives from
1,1-Dichloro-2-nitroethene and Hydrazides

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On-water, Catalyst-Free and Room-temperature Construction of
2-Aryl-1,3,4-oxadiazole Derivatives from 1,1-Dichloro-2-nitroethene
and Hydrazides
Fengjuan Zhu, Minming Zou, Xusheng Shao* and Zhong Li
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of
Science and Technology, Shanghai, 200237, China
Phone: +86ꢀ21ꢀ64253967. Fax: +86ꢀ21ꢀ64252603. Eꢀmail: shaoxusheng@ecust.edu.cn.
Abstract: 2ꢀArylꢀ1,3,4ꢀoxadiazoles are important functional molecules in many research fields. A
green synthetic method for preparation of 2ꢀarylꢀ1,3,4ꢀoxadiazoles was developed using
hydrazides and highly reactive 1,1ꢀdichloroꢀ2ꢀnitroethene. This ecoꢀfriendly protocol featured by
high yields, purification simplicity, waterꢀbased reaction medium, energy efficiency and no
addition of catalysts.
Introduction
The greening of synthetic methods has become one of the most important research topics in
organic chemistry in recent decades owing to the stringent concerns on environmental protection,
sustainable development and energy crisis.1 One of the twelve principles2 in green chemistry is using
safer solvents. Water meets the needs for an ideal solvent due to its fascinating properties such as
abundance, easy availability, high heat capacity, nonꢀtoxicity, nonflammability and redox stability.3
In addition, driving the reaction in void of catalysts is also long pursued by chemists to fulfill the
goal of greening. Thus, there is much interest in developing inꢀwater / onꢀwater4,5 or catalystꢀfree
synthetic methods with high efficiency, lowꢀenergy consumption and easy operation.
Arylꢀ1,3,4ꢀoxadiazoles (AODAs) are frequentlyꢀappeared intermediates or structural fragments in
organic and medicinal chemistry as well as in polymer and material science.6ꢀ8 Simply searching the
AODA as substructure in Scifinder, more than 120,000 results are presented relating to its
preparation as intermediates or final products. This high degree of concerns is attributed to their
involvement in a variety of biological compounds across many areas ranging from pharmaceuticals
to pesticides,9,10 such as cancer,7,11,12 diabetes,13 obesity,14 infection,15ꢀ18 insecticides,19 and
herbicides.20ꢀ22 Raltegravir,23 Tiodazosin,8 Nosapidil8,24 and Furamizole8,24 are oxadiazole derivatives
already presented in the market. Furthermore, this functionality has also been served as surrogates of
carbonyl containing compounds including carboxylic acid, esters amides, carbamates and
hydroxamic esters.25ꢀ27
In light of their importance, a number of different strategies have been developed for the
construction of AODAs. The most commonly used building blocks are hydrazides, which
underwent cyclization by phosphorus oxychloride,28,29 2ꢀchloroacetic acid,30,31 thionyl chloride,32
cyanic bromide33 and Burgess reagent.34 Milder reaction conditions were accomplished by
employing of phosphonium, dimethylimidazolinium chloride, PPh3 and bistriphenylphosphonium
ditriflate (PVꢀreagent).35 In recent years, some notable improvement to synthesize this heterocycle
scaffold can be summed up as cyclization of hydrazide with orthoformates catalyzed by

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ammonium chloride,36 Nafion catalyzed synthesis under microwave37 and sonochemical synthesis
from benzoic acid.38 However, most strategies suffered from one or more drawbacks which do not
fit the role of green chemistry, such as use of organic solvents and expensive catalysts, high
temperature, long reaction time, low yields, microwave irradiation and ultrasound acceleration.
Therefore, an urgent need exists to search for a versatile methodology for preparing AODAs in a
greener manner. Herein, we presented a novel way utilizing 1,1ꢀdichloroꢀ2ꢀnitroethene (DCNE) as
building blocks to efficiently synthesize AODAs. The reaction is characterized by onꢀwater,
catalystꢀfree, high yields and easy operation and purification.
Results and Discussion
DCNE is a reactive chemical intermediate, the strong electroꢀwithdrawing nitro makes the C=C
double bond highly polarized. The high polarized structure was confirmed on the basis of analysis
of electrophilicities of nitrothene.39ꢀ41 The calculation studies indicated that the electronic density
around the βꢀcarbon is lower than that in 1,2ꢀdichloroethylene, almost the same level with that in
phosgene (Fig. 1). Thus, the αꢀcarbon and the βꢀone can be easily attacked by nucleophiles and
electrophiles, respectively. When the reaction behavior of DCNE with hydrazides were explored,
we happily to found that the reaction proceeded smoothly affording AODA 5a with high
efficiency (Scheme 1).
We began by examining the model reaction of benzohydrazide (BHA) 4a with DCNE. The
solvents were firstly screened (Table 1). In this typical reaction, simple mixing of the two
reactants in various organic solvents at room temperature without catalysts gave the oxadiazole
products 5a instead of the threeꢀmembered 6. Furthermore, the structure of 5a was identified by
XꢀRay diffraction studies42 (Fig. 2). However, the yields were relatively low (20ꢀ60%) even the
reaction time was prolonged to 96 hours. No significant correlation of yields with solvent polarity
was observed. Toluene gave the highest yields reaching up to 58%. While in ethanol and methanol
the yields were quite low (around 20%). In order to fasten the reaction, the temperatureꢀyields
effect was then evaluated in toluene. Elevating the reaction temperature had dual effects, high
yields (95%) and reaction rates (2 h). Upon further investigation, we happily found that the
reaction proceeded very well when water was used as the reaction medium, with almost the
quantitative conversion (more than 90%). Moreover, the product precipitated from the reaction
mixture and can be easily separated by filtrate with good purity (97%). The acid capturer is
unnecessary to the high conversion, although two equivalent of hydrochloride acid generated
during the reaction. The reaction proceeded more rapidly at 50 °C furnishing the corresponding
AODA in excellent yields, but for energyꢀsaving consideration, this condition was not used for
further scopes study. Making it together, the advantages of using water as solvent are catalystꢀfree,
no side reaction, easy operation and purification and energy saving. Such a green strategy may
provide alternative for AODAs preparation. The success of using water as solvent might be due to
the low solubility of DCNE in water, which reduces its reactivity. Furthermore, the product
precipitated from the reaction mixture, which further drives this conversion.
Having the intriguing results above, the scope of this methodology was further explored (Table
2). In all cases, quantitative formation of AODAs was achieved upon simply stirring the reaction
mixture of DCNE and BHAs on water at room temperature. The structures of the AODAs were

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well characterized by 1H NMR, 13C NMR and HRMS study. A variety of functional groups such as
nitro, methyl, methoxy as well as halogens were all compatible with this transformation. Notably,
the paraꢀsubstituted (5d, 5g, 5i, 5l) BHAs also gave high yields, which was previously difficult to
be obtained in desired yields. The electron features or substitutedꢀpositions of the substituents in
BHAs had little influence on the efficiency of this protocol. Overall, the electronꢀdonating
substituents have favorable effects to the reaction, but the difference was not obvious compared
with the electronꢀwithdrawing ones. For the trimethoxyꢀsubstituted (5m) BHA, the yields were
relatively low probably due to the electron effects of three methoxy substituents.
For many substrates or groups are sensitive to water through degradation and hydrolysis, the
feasibility and high efficiency of this reaction were also verified in the organic solvents,
fortunately, the reaction proceeded well in the toluene with almost the same yields obtained on
water.
The change of the aromatic unit of BHA with heterocyclic one (Table 2, entry 14, 5n) did not
influence reactivity with a bit lower yields (85%), We were also pleased to find that the reaction
system could be successfully applied to isoꢀ and tereꢀphthalic dihydrazides (Table 2, entry 15 and
16, 5o, 5p, respectively) with high yields and purity. However, in case of dihydrazide substituted
at the orthoꢀposition (Table 3, entry 3), the phthalhydrazide was formed instead of corresponding
AODA due to the instability and easy cyclization of this kind of dihydrazide.
Reaction of the alkyl hydrazide (Table 3, entry 1) was unsuccessful with the complexation of
the reaction. Reaction of heterocyclic hydrazide thiopheneꢀ2ꢀcarbohydrazide proceeded well with
high yields. This phenomenon was also proved by other types of base such as TEA, DIPEA and
pyridine with the formation of brown or red salts.
Then we investigated the more complex hydrazides, such as phenylꢀsubstituted hydrazide
(Table 3, entry 4 and 5) and cyclic hydrazide (Table 3, entry 6), unfortunately, nitro acetylation of
the compound was observed. The possible formation of nitro acetylꢀproducts were depicted in
Scheme 2. In this proposed pathway, the cyclized intermediate C was formed followed by the
hydrolysis of the cycle due to the instability. This observation suggested that the primary amine
moiety is essential to the formation of AODA. Cyclic substrate 2ꢀaminoisoindolineꢀ1,3ꢀdione was
also explored affording the unseparated products (Table 3, entry 7).
In order to elucidate reaction pathways, the 1HNMR tracking of the model reaction in D2O was
1
studied. HNMR spectra in D2O collected during the course of the reaction only revealed the
consumption of BHA (Fig. 4). The increase of H2O peak at δ 4.74 indicated that the formation of
hydrogen chloride. This observation suggested that the formation of AODA occurred immediately
and no other intermediates formed during the process. Based on the observation from the current
study, a plausible reaction pathway was proposed (Scheme 2). The reaction was initiated by the
nucleophilic substitution of BHA to DCNE to give intermediate A which underwent
tautomerization affording B. The subsequent intramolecular nucleophilic attack occurred giving
intermediate C which tautomerized to final product.

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Fig. 1. Chemical structure of DCNE, phosgene and 1,1ꢀdichloroethene and their electron density
maps (electrostatic potential maps)
Scheme 1. Reaction of DCNE with benzohydrazide, a possible product
Fig. 2. crystal structure of 5a
Scheme 2. Possible mechanism of formation of AODA from DCNE and BHA

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Fig. 4. 1H NMR tracking of the formation of AODA

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Table 1. Optimization of the formation of AODA 5a
Entry Temp (°C)
Solvent
chloroform
dichloromethane
ethyl acetate
acetonitrile
THF
Time (h) Yield (%)
1
2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
96
96
96
96
96
96
96
96
96
96
53
53
53
24
2
52a
50a
48a
47a
43a
42a
40a
26a
20a
58a
49a
54a
76a
50a
95a
90b
90b
80b
3
4
5
6
1,2ꢀdichloroethane
acetone
7
8
ethanol
9
methanol
toluene
10
11
12
13
14
15
16
17
18
toluene
60
toluene
85
toluene
85
toluene
reflux
r.t.
50
toluene
H2O
12
3
H2O
80
H2O
3
aUPLC yield. bProduct was isolated by filtration.

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Table 2. Substrate scope investigation
Entry
Toluene/reflux
H2O/r.t.
Ar
5
Time (h)
Yield (%)
Time (h)
Yield (%)
90b
1
2
Ph
2ꢀNO2ꢀPh
3ꢀNO2ꢀPh
4ꢀNO2ꢀPh
2ꢀCH3ꢀPh
3ꢀCH3ꢀPh
4ꢀCH3ꢀPh
2ꢀFꢀPh
5a
5b
5c
5d
5e
5f
2
4.5
10
12
2
94
88
85
82
94
93
93
91
92
88
93
90
80
/
12
12
12
12
12
12
12
12
12
12
12
12
12
11
91b
3
93b
4
94b
5
92a
6
2
96b
7
5g
5h
5i
2
91b
8
2
90b
9
4ꢀFꢀPh
3
90b
10
11
12
13
14
3ꢀBrꢀPh
5j
7
88b
2ꢀClꢀPh
5k
5l
2
90a
4ꢀtertꢀBuꢀPh
3,4,5ꢀtrimethoxyꢀPh
2ꢀThienyl
2
90b
5m
5n
10
/
93b
85b
15
5o
/
/
12
12
92b
O
O
NHNH2
NHNH2
16
5p
/
/
92b
aProduct was isolated by column chromatography. bProduct was isolated by filtration.

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Table 3. Unsuccessful hydrazide substrates for AODA formation using water at room temperature
Entry
Hydrazide
Time
(h)
Product
Yield
(%)b
1
n.r.
_
n.r.
_
n.r.
_
2c
3
12
50
74
57
4
5
12
7a
O
N
N
NO2
H
O
F3C
6
12
_
45
_
7c
_
aH2O 55°C. bProduct was isolated by filtration. cunseparated products
Conclusion
In summary, we established a high efficient synthetic method for green synthesis of biologically
important 2ꢀarylꢀ1,3,4ꢀoxidiazoles via application of BHA and DCNE. The waterꢀbased and
catalystꢀfree reaction described here present several advantages over the exiting methods, which
meets the requirements for green chemistry. In addition, many natural products contain hydrazide
substructure, this new method may provide practicable derivertized procedure for these sensitive
natural molecules.

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Experimental
Melting points (mp) were recorded on Büchi B540 apparatus (Büchi Labortechnik AG, Flawil,
1
Switzerland) and are uncorrected. H NMR and 13C NMR spectra were recorded on Bruker
AMꢀ400 (1H at 400 MHz, 13C at 100 MHz) spectrometer with DMSOꢀd6 as the solvent and TMS
as the internal standard. Chemical shifts are reported in δ (parts per million) values.
Highꢀresolution electron mass spectra (ESIꢀTOF) were performed on a Micromass LCꢀTOF
spectrometer. Analytical thinꢀlayer chromatography (TLC) was carried out on precoated plates
(silica gel 60 F254), and spots were visualized with ultraviolet (UV) light. Chromatographic
analysis was performed using an ACQUITY UPLCꢀH Class system (Waters Corp., USA),
equipped with BEH C18 reversed phase column with 50 mm×2.1 mm i.d. and 1.7 ꢁm particle size,
equipped with a quaternary solvent delivery system, a 48ꢀvial autosampler (10 ꢁL loop), and a
photodiode array detector (PDA). The UPLC separations were carried out using gradient
separation at a flow rate of 0.4 mL minꢀ1. The mobile phase was a mixture of MilliQ ultrapure
water (A) and acetonitrile (B). The following elution gradient totally lasted 15 min: initial
mobileꢀphase composition, 90:10 (v/v) phase A:B; 0ꢀ3.5 min, linear change from 10 to 45% B;
3.5ꢀ7 min, linear change from 45 to 60% B; 7ꢀ8 min linear change from 60 to 100% B; 8ꢀ10 min
100% B; 10ꢀ11 min, 90:10 (v/v) phase A:B. The column and injection chamber were maintained at
40 and 25 °C, respectively. The sample injection volume was 3 ꢁL and the detector was set at 321
nm. Gaussian09 calculated the electron cloud density and Multiwfn plotted electron cloud density
map.
Procedure for the preparation of some hydrazides
Phthalohydrazide, N'ꢀphenylꢀ4ꢀ(trifluoromethyl)benzohydrazide and N'ꢀphenylbenzohydrazide
were synthesized according to the reported procedures.43,44
General procedure for the preparation of compounds
Toluene as the solvent: A mixture of hydrazide (1 mmol) and DCNE (1.2 mmol) in 10 mL toluene
was heated to reflux for 2ꢀ10 h. After completion of the reaction (TLC), the mixture was purified
by column chromatography eluting with petroleum ether / acetic ester (3:1) and afforded the
desired product.
Water as the solvent: A mixture of hydrazide (1 mmol) and DCNE (1.2 mmol) in 10 mL H2O was
stirred at room temperature or higher temperature for 7ꢀ12 h. After completion of the reaction
(TLC), the product precipitated from the reaction mixture and was separated by filtration.
Acknowledgements
This work was financial supported by National Natural Science Foundation of China (21372079,
21472046), National High Technology Research Development Program of China (863 Program,
2011AA10A207), Shanghai Pujiang Program (14PJD012) and the Fundamental Research Funds
for the Central Universities (222201414015), this work was also partly supported by Australia DC
Foundation.

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The image of Construction of 2ꢀArylꢀ1,3,4ꢀoxadiazole Derivatives from
1,1ꢀDichloroꢀ2ꢀnitroethene and Hydrazides