Synthesis of 5-substituted-3H-[1,3,4]-oxadiazol-2-one derivatives: A carbon dioxide route (CDR)

Article abstract of DOI:10.1039/c5ra08910g

A carbon dioxide route (CDR) for making biologically important 5-substituted-3H-[1,3,4]-oxadiazol-2-ones (SHOs) has been accomplished through synthesis and cyclization of a variety of hydrazides as the key intermediates. All of these hydrazides were prepared readily in 89-97% yields by reacting acid chlorides with a hydrazine monohydrate in the initial step. Then, SHOs were obtained in high yields from hydrazides by reacting them with carbon dioxide under basic conditions. More notable than the high yields, is that the present CDR process for the first time has succeeded in providing a straightforward cyclization reaction leading to SHO formation with simple reagents in ethanol solution.

Full text of DOI:10.1039/c5ra08910g

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Synthesis of 5-substituted-3H-[1, 3, 4]-oxadiazol-2-one derivatives: A carbon dioxide
route (CDR)
M.Brahmayya, Shenghong. A.Dai, S.Y.Suen*
Department of Chemical Engineering, National Chung Hsing University, KuoꢀKuang road, Taichungꢀ
402, Taiwan, ROC.
*Corresponding author: Prof.ShingꢀYi Suen, sysuen@dragon.nchu.edu.tw , Phone 886ꢀ4ꢀ2285 2590, Fax
886ꢀ4ꢀ2285 4734
The authors (coꢀfirst authors) contributed equally to this work
Abstract : A carbon dioxide route (CDR) of making biologically important 5ꢀsubstitutedꢀ3Hꢀ[1,3,4]ꢀ
oxadizoleꢀ2ꢀone (SHOs) has been accomplished through synthesis and cyclization of varieties of
hydrazides as their key intermediates. All these hydrazides were prepared readily in 95~98% by reacting
acid chlorides with hydrazine monohydrate in the initial step. Then, SHOs were obtained in high yields
from hydrazides by reacting them with carbon dioxide under basic conditions. More notable than high
yields, the present CDR process for the first time has succeeded in straightforward cyclization reaction
leading to SHOs formation with the simple reagents in ethanol solution.
Keywords: Carbon dioxide, Cyclization, 1, 3, 4ꢀOxadiazoles, Characterizations.
1. Introduction.1, 3, 4ꢀOxadiazole compounds represent a large family of biologically important 5ꢀ
membered heterocyclic intermediates, which were interesting the superlative to the synthetic chemists all
over the world 1ꢀ5. A huge number of 2, 5ꢀdisubstitutedꢀ[1, 3, 4]ꢀoxadiazole containing drugs have been
6
covering their significant roles in medicinal chemistry . In specific, the development of effective and
practical organic synthesis of 5ꢀ(aryl or alkyl)ꢀ3Hꢀ[1, 3, 4]ꢀoxadiazoles is a lively subject of organic
research work. In the sequence of our current work we have been becoming to show an interest in
preparation of 1, 3, 4ꢀoxadiazoles due to their versatile building blocks with a wide scope of biological
activities like, antiꢀinflammatory, antitubercular, antibacterial, antiviral, antipyretic, anticancer, central
nervous system depressants, antischistosomal, analgesic, antiemetic and anticonvulsive properties7. The

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famous use of heterocyclic intermediates is a scaffold in medicinal chemistry8.A number of 2, 5
disubstitutedꢀ[1,3,4]ꢀoxadiazoles have significant interest in polymer chemistry due to their luminescence
properties9.
Generally, synthetic procedures established on dehydrative cyclisation of semicarbazides, hydrazides are
frequently used and curiously involved a corrosive reagents such as concentrated sulfuric acid or POCl3,
boron trifluoride diethyl etherate or Burgess reagent, phosphorus oxychloride, polyphosphoric acid,
Thionyl chlorides where these conversely, results in an inflexible byproduct in the reaction and where the
examinations were inadequate and has no experimental diversity10ꢀ14. To avoid undesirable reagents in the
reaction, presently we have been focused our deep interest in the improvement in novel synthetic
strategies to obtain attractive functionalized oxadiazoles. In a determination to chemically stitch up these
biologically important heterocyclic molecules, we wanted to develop a modern synthetic route for the
preparation of 5ꢀsubstitutedꢀ3Hꢀ[1, 3, 4]ꢀoxadiazole 2ꢀone derivatives as a major chemical skeletons. We
have paid an attention to this CDR process for the cheaper price of reagents and efficient reaction
conditions without any byꢀproducts or any mishaps in handling of acidchlorides15ꢀ18. Moreover carbon
dioxide (CO2) is a nontoxic, an abundant, nonꢀflammable, easily available chief greenhouse gas and a
renewable carbon reservoir. To the best of our literature awareness, limited approaches existed for the
synthesis of 1, 3, 4ꢀoxadiazoles with the use of CO2 gas. Conversion of CO2 to useful organic and
inorganic products and is of an unlimited prominence from a scientific field16ꢀ19. In spite of many efforts
has been made to convert CO2, the diversity of reactions is inadequate since CO2 is thermodynamically
grooming and kinetically inactive20. The Investigation of these innovative reactions to the conversion of
carbon dioxide into an important organic product, which could support green and sustainability to this
methodology and easier to use in the industries instead of restricted reagents like morpholine21 and
chloroform22.The chemical fascination of carbondioxide through the cyclisation of several hydrazides
with CO2 to afford SHOs has been found to keep progress of various basic medium catalysts23. However,
the synthesis of SHOs and their analogues of CO2 and hydrazides have not been reported well. Herein, we

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discovered for the first time that atmospheric carbondioxide could react with hydrazides to generate
SHOs without any harsh conditions (Schemeꢀ2) at atmospheric CO2. Prepared samples were examined
with 1HNMR, IR, 13 C NMR and UVꢀVisible spectroscopy.
2. Materials and methods. All commercially available reagents and solvents were obtained from the
commercial suppliers and used without further purification. For the cyclisation reaction, all the
experiments were conducted in a 100 mL roundꢀbottomed Pyrex glass flask with continuous and constant
stirring speed at 600 rpm. Thin layer chromatography (TLC) was applied on silica gel plates. Flash
column chromatography was done by using 300ꢀ400 mesh type silica gels. Visualisation on TLC was
1
attained by illumination under UV lamp (254nm). HNMR spectra were recorded on a 400 MHz
spectrometer and 13C NMR was recorded on 100 MHz spectrometer using tetramethylsilane (TMS)
served as an internal standard. Infrared (IR) spectra were recorded with Perkin Elmer Spectrum One FTꢀ
IR spectrometer. Samples were prepared as potassium bromide pellets for IR characterizations. Highꢀ
resolution mass spectrometry, UVꢀvisible spectrum was recorded on UV–vis spectrophotometer (UVꢀ
1601, Shimadzu, Australia). (HRMS) was recorded. All of the substrates were prepared for the known
experimental procedures with minor modification.
2.1 Preparation of butanoyl hydrazide (scheme-1).
Some reports were wellꢀestablished for the synthesis of hydrazides but still there was a problem of
reaction handlings and experimental practices with those of highly reactive acid halides. Herewith, we
0
provided a very useful experimental methods and procedures at extremely lower temperature ꢀ10 C for
this well established reactions, which could be practical and useful (fig.1).
2.2 A careful experimental procedure for the preparation of hydrazides.
A neat and well dried 100 ml, threeꢀnecked roundꢀbottomed flask was fitted with a Teflonꢀcoated
thermocouple and containing magnetic beat inside the flask. 50ml of ethanol (98%) and sodium
hydroxide (0.35 g, 0.0087 mol) were charged into the flask. The magnetic paddle was started to stir

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continuously to mix the input chemical components to obtain a solution. An aqueous solution of
hydrazine monohydrate (98%, 0.40 gm, 0.008 mole) was added into the flask with standard precautions in
the fumingꢀcup board. This reaction mixture was cooled in an iceꢀmethanol/salt bath to attain an internal
cooling temperature of –10 to 0 °C. Before adding the butanoyl chloride to the reaction mixture, open one
neck of the flask to make sure an outlet for the simultaneous generated HCl gas vapours to go out into
cupboard. This can decrease higher pressure in the RBF, to avoid accidents. Then, start addition of a
benzoyl chloride (0.43 gm, 0.0034 mol) with help of a long range synerge needle, and where the needle’s
tip should be dipped in the reaction mixture by using correctly fitted rubberꢀseptum support from other
neck of RBF to make a steady flow rate into the reaction mixture over a period of one hour, keeping the
same cooling temperature (figꢀ1.a). A white solid suspended product has been formed within 5ꢀ10
minutes. This whole reaction mass is neutralised with 10% of sodium hydroxide (15 ml) solution only
due to the generated HCl gas always passed out from the open end of the reactor. So that the less quantity
of base is used. The reaction mixture was further taken into the ethyl acetate (20 ml) and then separated
out as organic layer. This was transferred to a 100 ml, single necked flask and concentrated to a volume
of ca.10 ml by rotary evaporation (at ca. 10mm) and finally the suspension was filtered and further
concentrated to 5 ml and add 25 ml of toluene and the resulting liquid is taken in doubleꢀnecked round
bottom flask which was equipped with a deanꢀstalk liquid separator, thermometer to separate out the
azeotropic mixtures at constant temperature 1100 C (figꢀ1.b). Finally, we found a shiny powder at the
bottom of RBF, after the complete evaporation of aqueous and organic solvents in the flask. This solid
product was recrystallized from 10mL of diethyl ether to obtain 0.38ꢀ0.395 gm (95ꢀ98%) of propyl
hydrazide. The completion of reaction was monitored by thin layer chromatography, Infrared spectrum
and 1HNMR. Compounds 3aꢀj were prepared with this method and then further used to synthesize SHOs.
Spectral data was summarized at supporting information S1ꢀS20.

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Figure 1.An experimental setup of schemeꢀ1 and schemeꢀ2 reactions
O
O
1) NaOH
R
NH2.NH2.H2O
NHNH2.H2O
R
Cl
2) -10 to 00
3) 5-10 min
C
60-65 %
Alkaloyl or aroyl halide Hydrazine (98%)
1a-j
Alkaloyl or aroyl hydrazide
3a-j
2
Scheme-1
2.3 Preparation of 5-(p-methoxy)-3H-[1, 3, 4]-oxadiazol-2-one
we had taken compound 3c (0.12 g, 0.0064 mol) was dissolved in the ethanol (10 ml) in a 100 ml three
necked round bottom flask with a magnetic beat inside to mix the reaction mass. The solution was
vigorously stirred. Then, further added a strong base KOH (0.37 g, 0.0044 mol), into the reactor and
stirred for 15 minutes to obtain a homogeneous solution in the flask under the room temperature. Pass the
carbon dioxide into the reactor through the other neck of the flask by using the help of gas purging glass
tube while its tip was dipped in reaction mixture and maintain the temperature at 50 0C for six hours (figꢀ
1.c). Then remove the CO2 inlet and close the reactor’s neck and reflux the reaction mass for 30 minutes
to obtain a crude product. This residual product was taken in 10ꢀ15 mL of water and quenched with dilute
HCl (10%). The precipitate was filtered off, dried and the yield was 95% (m.p 1100 C). It was further
taken into the ethanol and recrystallized. The completion of reaction was monitored by thin layer
chromatography and Infrared spectrophotometer.
The same procedure had been applied for the selected alkaloyl hydrazides (3j) or aroyl halides (3aꢀi) to
attain 5ꢀsubstitutedꢀ1,3,4ꢀoxadiazoleꢀ2ꢀones (4j) or (4aꢀi).

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3. Results and discussion.
3.1 Chemistry. The titled molecules were synthesized by the ring closure reactions to various alkaloyl or
aroylhydrazides (3aꢀj, schemeꢀ1) with carbon dioxide in the presence of potassium hydroxide in
excellence yields (4aꢀj,schemeꢀ2). The substrate hydrazides (3aꢀj) were synthesized by
dehydrochlorination of various aromatic and nonꢀaromatic acid chlorides with hydrazine monohydrate
under strong basic medium condition.
3.2. Synthesis. As a continuous effort in extent the application scope of 5ꢀmembered cyclisation
reactions, we intend to use oxadiazole compounds rather than isoxazoles 24. To our surprise, when the
reaction against hydrazine hydrate (2), acidchlorides (1aꢀj) was carried out in the presence of sodium
hydroxide at ꢀ100 C temperature instead of ꢀ5ꢀ00 C to afford hydrazide 3aꢀj within a 5ꢀ10 minutes. It
demonstrated that petty modified procedure for the synthesis of hydrazides is more naturally
approachable and useful than the known methods with our experimentally proved conditions (Tableꢀ1). It
is obvious that the basic medium plays an important role in this process. Hence, the possibility and the
limitation of this procedure explored for such a way of setting the temperature at ꢀ100 C and quantity of
the base is 0.0087 mol. All the selected acidchlorides (1aꢀj), such as alkaloyl or aroyl acid chlorides,
which were smoothly reacted with hydrazine hydrate and sodium hydroxide to afford the corresponding
hydrazides in good to excellent yields (Table 2) under the mentioned optimization conditions in Tableꢀ
1.The electron donating substituent groups on the aromatic acid chlorides did a slight influence on the
reaction to afford higher yields (tableꢀ2. entries 1, 3, 5, 6, 8).Whereas the electron withdrawing groups of
acid chlorides had been showed a slight decreasing yields on its corresponding final product (tableꢀ2,
entries 2, 4, 7, 9).Where as in the case of entry 10 (tableꢀ2), there was a positve inductive effect (+I)

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towards the nitrogen in its corresponding substrate (butanoyl chloride) resulted in the higher yield of
0
0
product. A variation of the reaction temperature from –10 C to 0 C shows a constructive influence on
both reaction rates and yield. It was noteworthy, the yields were not improved when the reaction was
carried out at 40 0C, RT, 0 0 C and ꢀ50 C, when it was compared at temperature ꢀ10 0 C.
Tableꢀ1.An optimal condition for the reaction of (pꢀmethyl)ꢀbenzoyl chloride and hydrazine monohydrate
to afford 3e.
Yield
Entry NaOH a (mol)
Temperature (0 C ) (%)
1
0.001
40
RT
0
None
10
2
0.001
3
0.001
70
4
0.0011
0.0018
0.002
0
74
5
ꢀ5
80
6
ꢀ5
83
7
0.004
ꢀ5
85
8
0.0060
0.0082
0.0087
ꢀ10
ꢀ10
ꢀ10
90
9
97
10
98
a The reaction was used under anhydrous NaOH.
Tableꢀ2: Synthesis of 3aꢀj by using the hydrazinemonohydrate with alkaloyl or aroyl halides.
Conversiona
Entry
R
Product
(%)
Yield (%)b
1
3a
96
94

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2
3
3b
3c
3d
90
98
93
90
96
89
4
5
6
3e
3f
98
96
96
92
7
8
3g
3h
95
99
91
97
9
3i
3j
96
97
93
95
10
Propyl
a, b Conversion and isolated yields were based on the NMR spsectroscopy.

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The compound butanoyl hydrazide formation was confirmed by its IR spectra (Fig. 2), 1HNMR spectrum
(fig.S19) and UVꢀanlaysis (Fig.4) monitoring. The same reaction conditions also have been applied
fruitfully to the synthesis of other aroyl hydrazides. All hydrazides prepared for this series were compiled
in Table 2.
3.3 Cyclisation of selected hydrazides into 1,3,4-oxadiazoles.
In 1998, J.R.Young showed a cyclisation reaction to aryl iodides with amidoximes under carbon
monoxide (CO) with palladium catalysts in tri ethylamine /organic solvent forming an oxadiazoles25ꢀ27
.
Nevertheless, the utilized reaction conditions and chemicals were not environmental benign and even
more expensive.
In this study we had improved the preparation and procedures to carry out the cyclisation of hydrazides
with greener carbon dioxide gas testing different reaction conditions to find the best way for the
production of oxadiazoles with the lowest price and with a greener reaction condition.
Afterwards of the obtaining acceptable results from the synthesis of corresponding acid hydrazides, we
then turned our attentions to the preparation of SHOs (4aꢀj).To do so, we have chosen a benzohydrazide
to optimize the reaction conditions carefully (schemeꢀ3). The effects of different reaction conditions were
investigated and summarized below in Tableꢀ3. From the literature survey, we fixed the ethanol was an
optimal solvent and potassium hydroxide as base. We were deeply focussed in quantity of potassium
hydroxide and temperature in the study of optimized conditions for the benzohydrazide to 5ꢀphenylꢀ3Hꢀ
0
[1, 3, 4]ꢀoxadiazolꢀ2ꢀone. We found that the conventional temperature is at 50 C. The required quantity
of potassium hydroxide is 0.0044 mol in the selected solvent ethanol under CDR procedure (Tableꢀ3).The
cyclization was carried by purging carbondioxide gas into the reactor, which contains the hydrazide,
potassium hydroxide and ethanol to obtain the title compounds at constant temperature 500 C with a
maximum time period of 6 hours. The scope of this simple CDR process was explored for using a
collection of structurally diverse organic acid chlorides and optimized with the benzohydrazide (schemeꢀ

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3) and tableꢀ3. Hydrazides reacted with carbon dioxide to form the organic intermediates 4aꢀj, which lost
a mole ratio of potassium hydroxide to afford the closedꢀring intermediate 4aꢀj.
Tableꢀ3. Optimization of reaction conditions for the synthesis of 5ꢀphenylꢀ3Hꢀ[1, 3, 4]ꢀ oxadiazoleꢀ2ꢀone
by using 3a.
Yield
Entry KOH a (mol)
Solvent
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Temperature (0 C ) (%)
1
0.001
0
None
10
2
3
4
5
6
0.001
RT
35
40
45
50
0.001
76
0.0044
0.0044
0.0044
73
91
96
a The reaction was monitored under anhydrous KOH.
Tableꢀ4.Syntheis of 5ꢀsubstitutedꢀ1,3,4 oxadiazoleꢀ2ꢀones
Corresponding
Entry
hydrazides
product
Time (hours)
Yield (%)
(3aꢀj of schemeꢀ1)
1
2
3a
3b
4a
4b
5
4
92
89

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3
4
3c
3d
3e
3f
3g
3h
3i
4c
4d
4e
4f
4g
4h
4i
5
6
6
6
6
6
6
6
95
95
93
90
87
93
90
95
5
6
7
8
9
10
3j
4j
Isolated yields were based proton NMR.
In all over the case studies, no difficulty was found whether the substrates are of active organic halides
(tableꢀ4, entries 1,3,5,6,8), which contained methyl, methoxy groups or the substrates of inactive organic
halides (tableꢀ4, entries 2, 4, 7), such as halo or nitro substituents on their corresponding phenyl rings
were used, the reactions proceeded smoothly to afford the desired SHOs (4aꢀj) in good at excellent yields.
All the resulting characterizations were completely matched with previous reports, and our technique is
an efficient and environmentally benign. The plausible reaction mechanism for the formation of 5ꢀ
susbstitutedꢀ3Hꢀ[1, 3, 4]ꢀoxadiaozlꢀ2ꢀones is proposed in Schemeꢀ4 (figꢀ5).
3.4. Characterizations.
The FTIRꢀspectra (fig.2) of unmodified hydrazinemonohydrate absorption peaks that were refer to
stretching of hydroxyl (ꢀOH), amine (ꢀNH) at wave numbers of 3400ꢀ3500 cmꢀ1, 3000 cmꢀ1(shifted to
lower than hydroxy due to the nearby regions of amine and hydroxyl groups) respectively. These data are
consistent with those of other studies29ꢀ30. Where as the one of our selected unmodified substrate butanoyl
chloride (1j) shows its absorption peaks of acyl (ꢀCOCl), aliphatic (ꢀCH2) at 1725ꢀ1700, 2982 cm−1
respectively. The product 3j shows its absorption peaks that refers to streching of amide (ꢀCONH), amine
(ꢀNH2), aliphatic (CH2) at 1610 cm−1, 3200 cm−1, 2980ꢀ2990 cm−1 respectively. The FTIR spectra (fig.3)
of the product 4j absorption peaks was assigned to amide at (ꢀCONH) 1625 cm−1, aliphatic (CH2 ) 2995

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cm−1, carbonyl (COONH) 1746 cm−1 and 3267ꢀ3600 cm−1 (mixed NH and any other hydroxy)
respectively. On the other hand the comparative studies of UV spectrum (fig.4) of compound 4j (5mg/10
ml ethanol) showed a distinguished splitted wavelength range of the visible region (200ꢀ330nm) rather
than the compounds hydrazinemonohydrate (2) (5mg in 10 mL in ethanol), butanoyl chloride (1j) (5mg in
10 mL of ethanol) , butyrohydrazide (3j) (5mg in 10 mL of ethanol) which shows their absorption at
below 200 nm (5mg in 10 mL of ethanol) and were consistent with literature30ꢀ31. When we had observed
the NMR results of 3aꢀj and 4aꢀj, those clearly indicating the significant chemical shift values of amidic (ꢀ
1
CONH) was at above 10 ppm for HNMR and 150ꢀ170 ppm in 13CNMR respectively, in both cases of
schemeꢀ1 and schemeꢀ2 analogues.We were summarized the all distinguished chemical shift values of
1
both HNMR and 13CNMR in the individual figures at supporting information (fig.S1ꢀS40) for all
synthesized compounds.
Figure 2.Comparative IRꢀSpectra of hydrazine monohydrate, butanoyl chloride and butanehydrazide.

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Figure 3.IRꢀspectrum of compound 4j.
Hydrazine (2)
butyrochloride (1j)
2
4j
Butyrohydrazide (3j)
5-porpyl-1,3,4 oxadiazole (4j)
4j
1j
3j
200
300
Wavelength (nm)
Figure 4. A Comparative UVꢀspectrum for hydrazinemonohydrate, butyrochloride, butyrohydrazide and
5ꢀpropylꢀ1,3,4ꢀoxadiazole.
3.5 Mechanism.
Finally, we found that the acid chlorides could be converted completely in a shorter time (5ꢀ10 minutes)
in each reaction (schemeꢀ1, tableꢀ2 and stepꢀ1 in figꢀ5). But a very long time i.e 4ꢀ6 hours was essential to
reach acceptable selectivity of the preferred product of (schemeꢀ2, tableꢀ4 and stepꢀ2 in figꢀ5).The time
(4ꢀ6 hours) required for the final product of 3aꢀj to 4aꢀj clearly indicating that the slower reaction. This
characteristic phenomenon could clear that the reactant is converted into the product of an intermediate
like potassium salt of 2ꢀoxyꢀ5ꢀ(aryl or alkyl)ꢀ1, 3, 4ꢀoxadiazoleꢀ2ꢀone as we proposed theoretical
assumption (plausible mechanism, figꢀ5). In this work, we studied the reaction of CO2 with hydrazides

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1
(3aꢀj) in detail and were confirmed by the results of HNMR,13C NMR (fig.S1ꢀS40) analysis and
consistency with all simulated and obtained data of some previous reports32ꢀ33
.
Figure 5.A plausible mechanism for the total sysnthesis.
4. Conclusions.
In summary, we have discovered a twoꢀstep synthetic process for the preparation of 5ꢀalkylꢀ3Hꢀ[1,3,4]ꢀ
oxadiazolꢀ2ones (SHOs) by using a simple CDR process, where the carbon dioxide can smoothly react
with hydrazides to form the targeted molecules at an atmospheric pressure under basic ethanol solution.
The reaction condition is mild, isolation of products is easy and the yields of SHOs are consistently high.
Hence, this novel CDR process might have great potentials for industrial applications.
5. Acknowledgements.
The authors are thankful to funding support under the scheme of NSCꢀ102ꢀ2221ꢀEꢀ005ꢀ065ꢀ
MY2, Taiwan.One of the author MBY special thanks to SꢀY.Suen and S.A.Dai.
6. Notes and references.
1.
F. Bentiss, M. Traisnel and M. Lagrenee, Corros. Sci., 2000, 42, 127ꢀ146.

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