One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles directly from nitrile and hydroxylamine hydrochloride under solvent-free conditions using potassium fluoride as catalyst and solid support

Article abstract of DOI:10.1080/00397910903370642

A one-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles with two identical substituents directly from the reaction of nitriles and hydroxylamine hydrochloride in the presence of potassium fluoride as catalyst and solid support under solvent-free condit

Full text of DOI:10.1080/00397910903370642

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One-Pot Synthesis of 3,5-Disubstituted
1,2,4-Oxadiazoles Directly from Nitrile
and Hydroxylamine Hydrochloride Under
Solvent-Free Conditions Using Potassium
Fluoride as Catalyst and Solid Support
Shahnaz Rostamizadeh a , Hamid Reza Ghaieni a b , Reza Aryan a &
Ali-Mohammad Amani a
a Department of Chemistry, K. N. Toosi University of Technology,
Tehran, Iran
b Faculty of Material and Chemical Engineering, Malek Ashtar
University of Technology, Tehran, Iran
Version of record first published: 13 Sep 2010
To cite this article: Shahnaz Rostamizadeh, Hamid Reza Ghaieni, Reza Aryan & Ali-Mohammad
Amani (2010): One-Pot Synthesis of 3,5-Disubstituted 1,2,4-Oxadiazoles Directly from Nitrile and
Hydroxylamine Hydrochloride Under Solvent-Free Conditions Using Potassium Fluoride as Catalyst
and Solid Support, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:20, 3084-3092
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Synthetic Communications1, 40: 3084–3092, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903370642
ONE-POT SYNTHESIS OF 3,5-DISUBSTITUTED
1,2,4-OXADIAZOLES DIRECTLY FROM NITRILE AND
HYDROXYLAMINE HYDROCHLORIDE UNDER
SOLVENT-FREE CONDITIONS USING POTASSIUM
FLUORIDE AS CATALYST AND SOLID SUPPORT
Shahnaz Rostamizadeh,1 Hamid Reza Ghaieni,1,2 Reza Aryan,1
and Ali-Mohammad Amani1
1Department of Chemistry, K. N. Toosi University of Technology,
Tehran, Iran
2Faculty of Material and Chemical Engineering, Malek Ashtar
University of Technology, Tehran, Iran
A one-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles with two identical substituents
directly from the reaction of nitriles and hydroxylamine hydrochloride in the presence of
potassium fluoride as catalyst and solid support under solvent-free condition is described.
Moreover, the formation of products has been discussed, and a plausible mechanism has
been presented. Simplicity of the process, workup in aqueous media, and excellent yields
are some advantages of this method.
Keywords: Amidoximes; nitriles; one-pot reaction; 1,2,4-oxadiazole; potassium fluoride; solvent-free condition
For reasons of economy and pollution prevention, solvent-free methods are of fun-
damental and growing interest and are used to modernize classical procedures
by making them cleaner, safer, and easier to perform. The demand for clean and
efficient chemical syntheses is becoming more urgent. The so-called green technolo-
gies are alternative ways to reduce drastic requirements for reactions. Among
proposed solutions, solvent-free conditions are popular. Now, it is often claimed that
‘‘the best solvent is no solvent.’’[1]
Among oxadiazoles, 1,2,4-oxadiazole derivatives have received increased
importance in medicinal chemistry. These compounds, when selectively functiona-
lized, have shown affinities for serotonin, norepinephrine transporters,[2] and urea
bioisostere in b3-adrenergic receptor agonists.[3]
Several methods have been reported in the literature for the synthesis of these
useful heterocycles.[4–10] Most commonly, they have been prepared by a two-step
process involving O-acylation of an amidoxime with an activated carboxylic acid
Received January 24, 2009.
Address correspondence to Shahnaz Rostamizadeh, Department of Chemistry, K. N. Toosi
University of Technology, P.O. Box 15875-4416, Tehran, Iran. E-mail: shrostamizadeh@yahoo.com
3084

DIRECT SYNTHESIS OF OXADIAZOLES FROM NITRILES
3085
Scheme 1. Main reaction pathway for the formation of 1,2,4-oxadiazoles.
derivative, typically an active acyl chloride, followed by cyclodehydration
(Scheme 1).
These methods, however, suffer from several drawbacks. Toxicity, high reac-
tivity of acid chlorides, difficult storage and handling, as well as limited commercial
availability of acid chlorides are major disadvantages of using these chemicals for
synthetic purposes. In addition, carboxylic acids need a coupling reagent such as
DCC, EDC, CDI, TBTU, HOBt, or HBTU to react with amidoximes. In these cases,
the reaction time is relatively long. Application of organic solvents during the main
process of synthesis and/or workup is also another deficiency of these methods from
the green chemistry point of view.[11]
Very recently, different methods have been reported for the synthesis of
1,2,4-oxadiazoles. Some of them include formation of these compounds under
microwave irradiation in the presence of solvent or under solvent-free conditions
in which amidoximes are required as starting materials.[12] Also, 3,5-disubstituted
1,2,4-oxadiazoles with two identical substituents were synthesized in ethylene glycol
with sodium carbonate under heating at 195 ꢀC for 30 h, in which a higher tempera-
ture and longer reaction time were required, but the proposed mechanism was not
completely described.[13] As shown in Scheme 2, for conversion of nitrile to amidox-
ime, we need basic (not acidic) media, because in acidic media the nitrile would
convert to an amide.[14]
Bases such as NaH or NaOEt at room temperature as well as pyridine with
heating[10] and tetrabutylammonium fluoride[15] in dichloromethane have been
reported for the cyclization and cyclodehydration of formed intermediates. There-
fore, it seems that strong bases can promote this reaction. To improve the method
used for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles with two identical sub-
stituents, we chose potassium fluoride as a strong base and solid support under
solvent-free conditions. Potassium fluoride has proven to be a versatile reagent in
many organic reactions such as decarboxylation,[16] Michael addition,[17] and various
Knoevenagel reactions.[18] The main advantage of using potassium fluoride is in the
ease of the workup process. An aqueous potassium fluoride solution can dissolve by-
products, such as amidoxime, and we are able to separate the pure 1,2,4-oxadiazole
from the reaction mixture by simple filtration. Almost all of the reported methods
for the conversion of nitriles to amidoximes require high temperatures under reflux
Scheme 2. Conversion of nitriles to amides and amidoximes in acidic and basic media.

3086
S. ROSTAMIZADEH ET AL.
Scheme 3. Potassium fluoride–catalyzed synthesis of 3,5-disubstituted 1,2,4-oxadiazoles with two identical
substituents.
conditions and long reaction times. Because of this and the safety profile of hydro-
xylamine hydrochloride,[19] we adjusted the reaction temperature to 100 ꢀC. Thus,
1,2,4-oxadiazoles were obtained in excellent yields and a good state of purity (under
this condition) using a strong base such as potassium fluoride (Scheme 3).
In the formation of 3,5-disubstituted 1,2,4-oxadiazoles with two identical sub-
stituents, three possibilities can be imagined:
1. Thermal decommission of amidoxime [Eq. (1)].
2. Reaction between nitrile and amidoxime [Eq. (2)].
3. Reaction of two amidoximes with each other [Eq. (3)].
Regarding the first equation, we found out that benzamidoxime melts at 80 ꢀC
and that it is stable up to 170 ꢀC. At this temperature, it decomposes, yielding several
products identified as nitrogen, nitrous oxide, ammonia, water, benzonitrile, benza-
mide, 3,5-diphenyl-1,2,4-oxadiazole, 3,5-diphenyl-l,2,4-triazole, and triphenyl-1,3,5-
triazine[10d] (Scheme 4). However, in our process, only 1,2,4-oxadiazole and a minor
amount of amidoxime were formed. Consequently, the hypothesis of the thermal
decomposition of amidoxime during the synthesis of 1,2,4-oxadiazole could be ruled
out this way.
To find out whether the formation of 1,2,4-oxadiazoles could result from the
reaction of an amidoxime and nitrile [Eq. (2)], we studied the effect of the amount
of hydroxylamine hydrochloride on the formation and the yield of 1,2,4-oxadiazoles.
Results are shown in Table 1.

DIRECT SYNTHESIS OF OXADIAZOLES FROM NITRILES
3087
Scheme 4. Thermal decomposition of benzamidoximes.
At the beginning of the reaction (after 1 h), all of the nitriles were converted to
amidoxime, and there was no nitriles left to react with amidoxime (Table 1, entry 1).
When the heating continued for 12 h, 1,2,4-oxadiazole was obtained in 88% yield
(Table 1, entry 2). In the presence of excess amounts of nitrile (2 mmol), the excess
nitriles did not enter the reaction and remained untouched until the end of the reac-
tion (Table 1, entry 3). Thus, the only possibility remaining is the reaction of two
amidoxime molecules with each other to give 3,5-disubstituted 1,2,4-oxadiazoles
with two identical groups [Eq. (3)].[20]
We also performed the reaction in the presence of different amounts of KF, and
application of 1 g potassium fluoride gave the best result. Any further increase in the
amount of potassium fluoride did not have much effect on the yield of the reaction
(Table 1, entry 4). It is reasonable to assume that at first the in situ formation of
amidoximes happened and then two molecules of amidoximes condensed with each
other to form the intermediate A. Then, this intermediate, under the reaction con-
ditions, was cyclized to disubstituted 4,5-dihydro-1,2,4-oxadiazoline intermediate B,
which was next aromatized to the final product C (Scheme 5). In fact, ammonia released
in the reaction mixture was observed as another proof for the proposed mechanism.
Table 1. Screening the effect of amount of NH2OH ꢁ HCl on the yield of 1,2,4-oxadiazolesa
KF
(mmol)
NH2OH ꢁ HCl
4-ClC6H5CNb
(mmol)
Entry
(mmol)
Amidoximeb (%)
1,2,4-Oxadiazoleb (%)
1
2
3
4
2
2
2
1
2
2
2
2
2
98c
8
—
88
40
90
2
2
1 (g)
7
8
aAll reactions were performed at 100 ꢀC for 12 h.
bIsolated yields.
c1 h after the reaction.

3088
S. ROSTAMIZADEH ET AL.
Scheme 5. Proposed mechanism for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles with two identical
substituents directly from nitrile.
To obtain further information and understand the effect of the nitrile on the
yield of 1,2,4-oxadiazoles, we chose a variety of structurally divergent benzonitriles
possessing a wide range of functional groups, the results of which are summarized in
Table 2. Among the various nitriles tested, the haloaromatics gave good yields
(Table 2, entries 2–5). The interesting point about haloaromatics is that nitriles with
substituents on position 4 of the ring relative to the cyano moiety react more
efficiently than those with substituents on positions 2 and 3.
It is worth mentioning that electron-donating groups (Table 2, entries 6–8)
reduced the rate of the formation of 1,2,4-oxadiazole. So, it seems that electronic effects
play a major role in this process. The reaction was also performed with aliphatic nitriles
where the reaction yield was low (Table 2, entry 9). Also, the reaction did not give
good results with o-hydroxy and o-amino benzonitriles (Table 2, entries 10 and 11).
Table 2. Effect of substituents on the yield of formation of disubstituted 1,2,4-oxadiazolea
Melting point (ꢀC)
Entry
R1
C6H5ꢂ
Yieldsb (%)
Found
Reported
1
2
75
90
106–108
183–184
189–190
93–94
141–142
104–105
127–128
126–127
—
109–110[21]
183[13]
4-ClC6H4ꢂ
4-BrC6H4ꢂ
2-ClC6H4ꢂ
3-ClC6H4ꢂ
4-CH3C6H4ꢂ
4-CH3OC6H4ꢂ
4-FC6H4ꢂ
3
92
85
189–190[22]
93–93[21]
141–142[21]
104–105[21]
128–129[13]
—
4
5
89
65
6
7
60
75
8
9
C6H5CH2ꢂ
2-OHC6H4ꢂ
2-NH2C6H4ꢂ
Low
—
—
—
10
11
—
—
—
—
aAll reactions were performed with 2 mmol nitrile, 2 mmol hydroxylamine hydrochloride, and 1 g
potassium fluoride at 100 ꢀC for 12 h.
bIsolated yields.

DIRECT SYNTHESIS OF OXADIAZOLES FROM NITRILES
3089
Additionally, the reaction was performed with weaker bases such as potassium
carbonate and sodium bicarbonate, with a yield lower than that of potassium
fluoride.
In conclusion, we have developed a solvent-free one-pot reaction for the
preparation of 3,5-disubstituted 1,2,4-oxadiazoles with two identical substituents.
Excellent yields, a simple purification process, short reaction times, and no use of
carboxylic acid derivatives are the main advantages of this method.
EXPERIMENTAL
General Procedure for the Synthesis of 3,5-Disubstituted
1,2,4-Oxadiazoles with Two Identical Substituents
Aramatic nitrile (2 mmol, 0.275 g), hydroxylamine hydrochloride (2 mmol,
0.138 g, finely ground), and potassium fluoride (1 g) were mixed thoroughly in a mor-
tar and pestle by grinding to form a homogeneous mixture. This mixture was then
heated at 100 ꢀC while being stirred for 12 h. Then, the mixture was cooled, and
water (10 ml) was added. The mixture was filtered with a Buchi funnel, washed with
water (30 ml), and dried at 60 ꢀC. The residues were further recrystallized from EtOH
96%. The product was obtained as colorless crystals.
Yields and melting points are shown in Table 2.
Spectral Data
3,5-Bis(phenyl)-1,2,4-oxadiazole (Table 2, entry 1). IR (KBr, cmꢂ1): 2921,
1
1606, 1560; H NMR (300 MHz, DMSO-d6) d 7.56–7.76 (6H, m, 6CH), 8.07–8.19
(4H, m, 4CH); 13C NMR (75 MHz, DMSO-d6) d 175.43 (C1), 126.13 (C2), 129.58
(C3), 129.29 (C4), 133.38 (C5), 129.29 (C6), 129.58 (C7), 168.26 (C8), 123.35 (C9),
127.92 (C10), 127.10 (C11), 131.69 (C12), 127.10 (C13), 127.92 (C14).
3,5-Bis(4-chlorophenyl)-1,2,4-oxadiazole (Table 2, entry 2). IR (KBr,
cmꢂ1): 2921, 1606, 1555, 1488; 1H NMR (300 MHz, DMSO-d6) d 7.67 (d, 2H,
J ¼ 8.3 Hz, 2CH), 7.74 (d, 2H, J ¼ 8.3 Hz, 2CH), d 8.08 (d, 2H, J ¼ 8.2 Hz, 2CH),
d 8.18 (d, 2H, J ¼ 8.2 Hz, 2CH); 13C NMR (75 MHz, DMSO-d6) d 174.82 (C1),
124.89 (C2), 129.79 (C3), 129.82 (C4), 138.34 (C5), 129.82 (C6), 129.79 (C7), 167.56
(C8), 122.14 (C9), 129.53 (C10), 128.94 (C11), 136.50 (C12), 128.94 (C13), 129.53 (C14).
3,5-Bis(4-bromophenyl)-1,2,4-oxadiazole (Table 2, entry 3). IR (KBr,
cmꢂ1): 2922, 1599, 1552, 1480; 1H NMR (300 MHz, DMSO-d6) d 7.80 (d, 2H,

3090
S. ROSTAMIZADEH ET AL.
J ¼ 8.5 Hz, 2CH), 7.87 (d, 2H, J ¼ 8.5 Hz, 2CH), d 8.01 (d, 2H, J ¼ 8.5 Hz, 2CH), d
8.10 (d, 2H, J ¼ 8.5 Hz, 2CH); 13C NMR (75 MHz, DMSO-d6) d 174.94 (C1), 125.20
(C2), 132.71 (C3), 132.45 (C4), 127.38 (C5), 132.45 (C6), 132.71 (C7), 167.66 (C8),
122.43 (C9), 129.86 (C10), 129.07 (C11), 125.35 (C12), 129.07 (C13), 129.86 (C14).
3,5-Bis(2-chlorophenyl)-1,2,4-oxadiazole (Table 2, entry 4). IR (KBr,
cmꢂ1): 2921, 1606, 1555; 1H NMR (300 MHz, DMSO-d6) d 7.55–7.65 (m, 3H,
3CH), 7.67–7.99 (m, 3H, 3CH), 8.01 (dd, 1H, J1 ¼ 7.5 Hz, J2 ¼ 1.9 Hz, 1CH), 8.18
(dd, 1H, J1 ¼ 7.7 Hz, J2 ¼ 1.65 Hz, 1CH); 13C NMR (75 MHz, DMSO-d6) d 174.25
(C1), 125.21 (C2), 132.43 (C3), 134.43 (C4), 132.83 (C5), 132.23 (C6), 131.89 (C7),
166.89 (C8), 122.46 (C9), 125.21 (C10), 127.79 (C11), 128.09 (C12), 130.92 (C13),
132.51 (C14).
3,5-Bis(3-chlorophenyl)-1,2,4-oxadiazole (Table 2, entry 5). IR (KBr,
1
cmꢂ1): 2921, 1608, 1555, 1478; H NMR (300 MHz, DMSO-d6) d 7.62–7.73 (m,
3H, 3CH), 7.80–7.84 (m, 1H, 1CH), 8.04–8.08 (m, 2H, 2CH), 8.14– 8.21 (m, 2H,
2CH); 13C NMR (75 MHz, DMSO-d6) d 174.53 (C1), 133.31 (C2), 134.20 (C3),
125.09 (C4), 134.00 (C5), 131.70 (C6), 131.44 (C7), 167.32 (C8), 131.65 (C9), 127.93
(C10), 127.79 (C11), 126.70 (C12), 126.73 (C13), 127.51 (C14).
3,5-Bis(4-metylphenyl)-1,2,4-oxadiazole (Table 2, entry 6). IR (KBr, cmꢂ1):
1
3028, 2955, 1608, 1558, 1490; H NMR (300 MHz, DMSO-d6) d 2.37 (s, 3H, CH3),
2.40 (s, 3H, CH3), 7.37 (d, 2H, J ¼ 8.0 Hz, 2CH), 7.43 (d, 2H, J ¼ 8.0 Hz,
2CH), d 7.95 (d, 2H, J ¼ 8.1 Hz, 2CH), d 8.03 (d, 2H, J ¼ 8.1 Hz, 2CH); 13C NMR
(75 MHz, DMSO-d6) d 175.29 (C1), 123.41 (C2), 130.07 (C3), 129.76 (C4), 143.71
(C5), 129.76 (C6), 130.07 (C7), 168.11 (C8), 120.68 (C9), 127.82 (C10), 127.00 (C11),
141.52 (C12), 127.00 (C13), 127.82 (C14).
3,5-Bis(4-flourophenyl)-1,2,4-oxadiazole (Table 2, entry 8). Milky crys-
1
tal; H NMR (300 MHz, DMSO-d6) d 7.43–7.46 (2H, m, 2CH), 7.50–7.53 (2H, m,
2CH), 8.13–8.16 (2H, m, 2CH), 8.25–8.28 (2H, m, 2CH); 13C NMR (75 MHz,
DMSO-d6) d 176.37 (C1), 124.16 (C2), 134.28 (C3), 130.44 (C4), 165.89 (C5),
130.44 (C6), 134.28 (C7), 168.34 (C8), 123.61 (C9), 128.79 (C10), 117.23 (C11),
161.20 (C12), 117.23 (C13), 128.79 (C14); MS (70 ev) m/z (%): 258 (Mþ, 94%), 137
(100%), 109 (43%), 95 (29%).
ACKNOWLEDGMENT
The authors gratefully acknowledge the Research Council of K. N. Toosi
University of Technology for partial financial support of this work.
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