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Diverse Synthetic Approaches to Design and Develop Oxadiazole-Based ... 3

2.2 Pd Catalyzed Oxadiazole Synthesis

In 2014, ataluren (medication for Duchenne muscular dystrophy) was approved

by the European Medicines Agency (EMA). Andersen et al. utilized a palladium

catalyst to synthesize ataluren drug 3b (Andersen et al. 2014). The reaction employed

3-cyanobenzoic acid as the starting material, where the carboxylic acid was protected

in the presence of boc anhydride (Scheme 3), and the terminal cyano group reacted

in the presence of hydroxylamine to yield the corresponding amidoxime in 94%

synthetic yield. The reaction facilitated the coupling of aryl bromide with amidoxime,

resulting in 1,2,4-oxadiazoles in excellent yields. The protected tert-butyl group (in

the case of 3a) was removed using trifluoroacetic acid (TFA) in dichloromethane.

HOOC

BuO

COOR

3a.

Bu,

74%

yield

(

Ataluren

yield

Boc

DMAP

DCM,

RT,

12h

63%

(aq.)

i-PrOH,

12h

94%

[Pd(allyl)Cl]

(1.5

mol

HBF

P(tBu)

mol%)

(1.4

equiv.)

toluene,

105

16h

3-cyanobenzoic

acid

TFA

Scheme 3. Synthesis of oxadiazole derivative 3a–b.

2.3 Solid Phase-Based Synthesis of 1,2,4-Oxadiazole Derivative

Oxadiazoles have also been prepared using solid support (Sams and Lau 1999; Makara

et al. 2002; Hu et al. 2008). The chemical reaction through solid-phase synthesis

provides high efficiency as well as increased speed of the reaction. Scientists at Trega

Biosciences (United States) led by Hébert et al. developed a series of oxadiazole

derivatives on solid support starting from aliphatic and aromatic nitriles (Hébert

et al. 1999). The authors utilized methylbenzhydryl amine (MBHA) resin during

synthesis. The reaction of resin-bound nitriles in the presence of hydroxylamine

hydrochloride (Scheme 4) and N, N-Diisopropylethylamine produced amide oxime

intermediate. Subsequent reaction with a boc-protected amino acid anhydride and

heating in the presence of 2-methoxyethyl ether yielded oxadiazole 4 in 95% yield.

The purity of the synthesized product was subjected to exact synthetic protocol.

Acylation of amide oxime required 60°C. The remaining amount of unreacted amino

acid anhydride washed away, resulting in a robust synthetic tool.

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Boc-AA-COOH

2-methoxy

ethyl ether

HN PG

OH.HCl,

DIEA

DIC,

OCH

2-methoxy

ethyl ether

16h

RT,

then

16h

-Ph-

-CH

Scheme 4. Synthesis of oxadiazole derivative 4.

DDQ

equiv.)

DMF,

150

min

73%

Scheme 5. Synthesis of oxadiazole derivative 5.

4 Oxadiazole in Material and Medicinal Chemistry

2.4 1,2,4-Oxadiazole Synthesis Using Oxidants

2.4.1 DDQ as Oxidant

Rapid and straightforward preparation of 1,2,4-oxadiazole has also been made

possible by introducing oxidants such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

(DDQ). Parker and Pierce at North Carolina State University utilized DDQ to

synthesize oxadiazole scaffold 5 from the corresponding amidoxime (Parker and

Pierce 2016). A diverse set of 1,2,4-oxadiazoles was prepared from a range of aryl,

alkyl, and heteroaryl substrates. The formation of oxadiazole involved two oxidation

steps where one equivalent of DDQ promoted oxadiazole synthesis in 34% yield

(Scheme 5). The introduction of another equivalent of DDQ increased the synthetic

yield of oxadiazole from 34% to 48%. However, utilization of more than 2 equivalents

of DDQ decreased the yield of reaction, indicating 2 equivalents of DDQ as the

optimized condition.

2.4.2 O

as Oxidants

Aerobic synthesis of 1,2,4-oxadiazole has been achieved by Zhang et al. in an O

atmosphere using N-benzyl amidoxime in 2013 (Zhang et al. 2013). Kuram et al.

isolated oxadiazole 6 in 92% yield utilizing CuI and O

(Schemes 6–7) through

an oxidative NO bond formation method (Kuram et al. 2016). This single-step

synthetic process could transform amides and organic nitriles to their respective

1,2,4-oxadiazole scaffolds. Reaction yield increased to 22% in the presence of a base

such as K

. Similarly, the introduction of various nitrogen ligands was checked,

and it was found that bathophenanthroline could increase the yield of the reaction up

to 36%. Very interestingly, the addition of ZnI

increased the yield of the reaction

up to 92%. Aromatic nitriles were found to be more reactive in comparison to their

aliphatic counterpart.

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CuI

(10

mol%)

Ligand

(10

mol%)

equiv.)

ZnI

(10

mol%)

atm)

Ligand:

Scheme 6. Synthesis of oxadiazole derivative 6.

PhH

Ph N

III

Ph N Ph

N Ph

N N

Ph N Ph

Scheme 7. Mechanism for the synthesis of oxadiazole (Kuram et al. 2016).

mol%

CN,

Blue

LEDs

PC:

ClO

Scheme 8. Synthesis of oxadiazole derivative 7.

Diverse Synthetic Approaches to Design and Develop Oxadiazole-Based ... 5

2.5 Visible Light Promoted 1,2,4-Oxadiazole Synthesis

Cai et al. developed a method for synthesizing 1,2,4-oxadiazole derivative 7

facilitated by visible light (Cai et al. 2019). In this method, substituted 2H-azirines

could react with nitrosoarenes and produce 1,2,4-oxadiazole through [3+2]

cycloaddition reaction (Scheme 8). Nitrosoarenes acted as appropriate radical

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6 Oxadiazole in Material and Medicinal Chemistry

acceptors during the reaction. Also, 9-Mesityl-10-methylacridinium perchlorate is

a well-known photo redox catalyst (PC) that promotes green synthesis of various

chemical transformations assisted with visible light.

3. Synthesis of 1,3,4-Oxadiazole Derivatives

3.1 POCl

-Promoted Oxadiazole Synthesis

Phosphoryl chloride promotes cyclization of reactions apart from its role in

chlorination. Wang et al. synthesized oxadiazole derivative 8 in four synthetic steps

utilizing pyridine-2,5-dicarboxylic acid (Wang et al. 2001). This synthetic process

involved the methylation of carboxylic acid followed by a reaction with hydrazine

hydrate (Scheme 9) to produce the corresponding hydrazide. It further reacted with

4-tertbutyl benzoyl chloride, subsequently reacted with phosphoryl chloride, and

neutralized with concentrated NaOH solution to produce the oxadiazole compound

8 in 53% yield.

To find suitable bioisostere, Mohammed et al. synthesized oxadiazole derivative

9 as part of optimization studies (Mohammed et al. 2016). 2-Iodobenzoic acid acted

as the starting precursor, reacting with thionyl chloride (Scheme 10) and hydrazine

hydrate to produce the corresponding hydrazide intermediate. Further, the hydrazide

intermediate reacted with 2-methyoxy benzoic acid in the presence of POCl

and

produced the oxadiazole intermediate. Finally, it reacted with 4-nitrothiophenol in

the presence of potassium carbonate and yielded compound 9.

In 2009, researchers at Syngene International Limited utilized propylphosphonic

anhydride (T3P) to synthesize 1,3,4-oxadiazole derivatives (Augustine et al.

2009). This one-pot synthetic step involved the reaction of various carboxylic acid

precursors with aryl hydrazides. Substituted acid hydrazide in the presence of CS

(carbon disulfide) and potassium hydroxide engaged in heterocyclic ring-closing and

forms an oxadiazole scaffold from an ethanolic solution (Kaplancikli 2011).

OHO

O OMe

OMe

MeOH/H

NHNH

EtOH

Pyridine

POCl

Scheme 9. Synthesis of oxadiazole derivative 8.

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I Br N

[PdCl

(PPh

)

]

CuI,

THF,

NaOH,

toluene

reflux

[PdCl

(PPh

)

]

CuI,

THF,

Scheme 11. Synthesis of oxadiazole derivative 10.

Diverse Synthetic Approaches to Design and Develop Oxadiazole-Based ... 7

COOH

SOCl

DMF(cat.)

benzene,

MeOH,

C-RT,

-anisic acid,

POCl

110

DMF,

110

mol%,

CuI,

Scheme 10. Synthesis of oxadiazole derivative 9.

3.2 Pd Catalyzed Oxadiazole Synthesis

In order to study the effect of oligomers on semiconducting properties, Lee et al.

synthesized a series of oxadiazole scaffolds utilizing coupling chemistry (Lee et al.

2009). These hybrid compounds could be useful for applications of OFET (organic

field effect transistor).

The reaction of 4-bromo-4’-iodobiphenyl, in the presence of diphenylamine,

induced diphenyl amine capped intermediate in 71% yield. After that, it underwent a

coupling reaction with Pd(PPh

)

and copper(I) iodide (Scheme 11), followed by a

reaction with NaOH to produce 4-(N, N-Diphenylamino)phenyl-4’-ethynylbiphenyl

in 70% yield (Pålsson et al. 2010). Further coupling with Pd(PPh

)

in the

presence of copper(I) iodide afforded target oxadiazole compound 10 in 42% yield.

3.3 Microwave-Assisted Synthesis

Wang et al. synthesized oxadiazole 11 from a reaction of biphenyl-4-carboxylic

acid with benzamide under microwave heating (Scheme 12) at 150°C in 85% yield

(Wang et al. 2006). Microwave heating, along with solid-phase reagents, improved

the purification process. In 2020, the reaction of isothiocyanates and hydrazides in

https://t.me/med1917

equiv.

DMC

equiv.

PS-BEMP

CN,

150

min

N N

DMC:

PS-BEMP

Scheme 12. Synthesis of oxadiazole derivative 11.

Cl Cl

O O

Acetone

O O

24h

DMF,

100

NaN

P P

O O

Pyridine

110

Scheme 13. Synthesis of oxadiazole derivative 12.

8 Oxadiazole in Material and Medicinal Chemistry

the presence of tert-butyl hydroperoxide (TBHP) and microwave heating resulted in

2-amino 1,3,4-oxadiazole in water (Kumar Sigalapalli et al. 2020).

In late 2010, Liu et al. synthesized cyclotriphosphazene-centered oxadiazole 12

in 61% yield through a three-step process (Liu et al. 2011). Hexachlorophosphazene,

in the presence of 4-cyanophenol and K

, produced an intermediate

hexakis(4-cyanophenyl)-cyclotriphosphazene (Scheme 13). The cyano intermediate

further reacted in the presence of sodium azide and ammonium chloride to produce

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Diverse Synthetic Approaches to Design and Develop Oxadiazole-Based ... 9

hexakis(4-tetrazolylphenyloxy)-cyclotriphosphazene in 89% yield. Finally, the

tetrazole intermediate reacted with benzoyl chloride in pyridine to yield the target

compound 12.

3.4 Solid Phase-Based Synthesis of 1,3,4-Oxadiazole Derivative

The solid-phase synthetic technique is a rapid preparation tool for a diverse range of

chemical products. It usually provides straightforward separation and purification

where impurities can be separated through filtration. In 2005, Severinsen et al.

developed a method for the construction of alkyl/arylamino-[1,3,4]-oxadiazoles in

high yields utilizing resin-bound semicarbazides in three synthetic steps (Severinsen

et al. 2005). In 2007, vinyl-substituted oxadiazole derivatives were synthesized using

polymer-based selenium resin with high-purity isolated products (Wang et al. 2007).

In 2005, Baxendale et al. successfully tailored a series of 5-substituted-2-amino-

1,3,4-oxadiazoles from a combination of three different starting materials such as

acylhydrazine, sulfonyl chloride, and an isocyanate and in the presence of polymer

assisted phosphazine base (Baxendale et al. 2005).

Similar to conventional synthetic methods, resin-bound organic scaffolds can

undergo chemical transformation to give a diverse range of useful products. In

2006, Liu et al. synthesized 1,3,4-oxadiazole derivative 13 utilizing resin-bound

intermediates (Scheme 14) (Liu et al. 2006). Later coupling of Fmoc-attached amino

acid with thiosemicarbazide resin resulted in 1,3,4-oxadiazoles in 2018 (Abdildinova

et al. 2018). Derivatization of amino acids on both sides yielded a range of compounds

useful for peptidomimetics.

Scheme 14. Synthesis of oxadiazole derivative 13.

NaO

DMF

Hydrazine hydrate

HMPA,

KOH

HCl

NaOH

(aq.)

MeI

SMe

TFA/DCM

3.5 Iodine-Promoted Synthesis of 1,3,4-Oxadiazole Derivative

Cheaper, accessible reagents play a vital role in executing large-scale organic

reactions. Molecular iodine is one such reagent that is available at a low cost and

plays a significant role in oxadiazole synthesis through C-O bond formation, such as

during the reaction of aldehydes with hydrazides.

One-pot cyclization of 4-phenylsemicarbazide with substituted aryl methyl

ketone was achieved by Zhang et al. (2022). I

/DMSO facilitated the cyclization

process in an oxidative environment and produced compound 14 in 80% yield with

as a base. Initially, reaction with I

ensured the formation of -iodo ketone

(Schemes 15–16).

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H H

DMSO

N N

16h

Scheme 15. Synthesis of oxadiazole derivative 14.

10 Oxadiazole in Material and Medicinal Chemistry

Scheme 16. Mechanism for the synthesis of oxadiazole derivative 14 (Zhang et al. 2022).

Komblum oxidation

DMSO

A B

N N

base

N N

base

-H

3.6 1,3,4-Oxadiazole Synthesis Using Oxidants

Like 1,2,4-oxadiazole synthesis, various oxidizing agents can also facilitate the

construction of 1,3,4-oxadiazole derivatives. In 2015, Wang et al. reported the

synthesis of 1,3,4-oxadiazole during a reaction of aryl tetrazole and an aryl aldehyde

using Di-tert-butyl peroxide (DTBP) as an oxidant (Wang et al. 2015). This one-pot

reaction proceeded with N-acylation of tetrazole substituent, and it was subjected to

thermal rearrangement to construct the cyclic oxadiazole ring in moderate to high

yields. A combination of arylacetic acid with substituted hydrazides in the presence

of K

can yield 2,5-disubstituted 1,3,4-oxadiazole scaffolds in an oxygen

environment (Lekkala et al. 2022). At first, this reaction undergoes an oxidative

decarboxylation process of arylacetic acid and later an oxidative functionalization

of imine C-H bonds to generate oxadiazole derivatives in up to 92% yield. In situ

formation of tert-butyl hypoiodite (t-BuOI) from t-BuOCl and NaI could be useful

for cyclization of N-acylhydrazones to generate substituted oxadiazoles (Gao and

Wei 2013).

3.7 Visible Light Promoted 1,3,4-Oxadiazole Synthesis

Visible light is often considered a clean and effective source of energy; the introduction

of visible light unravels new chemical reactions with excellent selectivity. In an

effort to achieve an efficient method for 1,3,4-oxadiazole synthesis, Kapoorr et al.

utilized visible light to transform semicarbazones into oxadiazole 15 in the presence

of a popular photoredox catalyst called “eosin Y” (Kapoorr et al. 2015). CBr

was

used as a brominating source (Schemes 17–18).

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CBr

Eosin

air

N NH

green

LEDs

CN,

RT,

10h

Eosin

Scheme 17. Synthesis of oxadiazole derivative 15.

Green

LEDs

COO

CBr

eosin

N NH

air,

green

LEDs

CN,

RT,

10-14h

N N

eosin

visible

light

eosin

CBr

HBr

CHBr

Diverse Synthetic Approaches to Design and Develop Oxadiazole-Based ... 11

Scheme 18. Mechanism for synthesis of oxadiazole derivative 15 (Kapoorr et al. 2015).

Recently, a combination of aryl aldehyde with hypervalent iodine (III) reagent

in the presence of visible light irradiation induced the formation of 2,5-disubstituted

1,3,4-oxadiazole derivatives in up to 89% yields (Li et al. 2021). Interestingly, the

reaction requires neither an additional catalyst nor the pre-activation of aldehydes.

Applying photocatalyst eosin Y into a solution of hydrazides and substituted

diketones resulted in 1,3,4-oxadiazole scaffolds in moderate to good yields (Diao

et al. 2018). The introduction of photocatalysts facilitated decarboxylation and

cyclization, leading to oxadiazole formation. Visible light can also be useful

for transforming multicomponent starting materials into their respective target

molecules. In 2021, Russo et al. summarized the preparation of 1,3,4-oxadiazole

derivatives utilizing a combination of carboxylic acids, N-alkyl-N-methylanilines,

and N-isocyanoiminotriphenylphosphorane in the presence of 30 W blue LED light

irradiation. N, N-dimethylaniline was oxidized to iminium cation promoted by a

ruthenium photocatalyst. The reaction resulted in the formation of three new bonds

(such as C-C, C-O, and C-N bonds) in the single reaction, and it could also tolerate a

variety of functional groups (Russo et al. 2021).

https://t.me/med1917

NHCONH

.HCl

PPA

tBDMSCl

imidazole

DMAP

monomer

t-BOC

O O

Pd(0)

B B

THF

O O

TFA

190

R1:

C18H17

R2:

and

t-BOC

mixed

(mole

ratio

5:5)

Scheme 19. Synthesis of oxadiazole derivatives 16–20.

12 Oxadiazole in Material and Medicinal Chemistry

3.8 Polymer-Based 1,3,4-Oxadiazole Derivative Synthesis

Thermally stable polymers with no decomposition below 386°C based on oxadiazole

motifs were fabricated by Chen et al. (1999). The introduction of poly(p-phenylene

vinylene) unit in the polymeric backbone assists in maintaining morphological

stability during the preparation of thin films. Later, in 2002, Ding et al. synthesized

various copolymers by installing alternating 9,9-dioctylfluorene and oxadiazole units

through a Suzuki cross-coupling reaction (Ding et al. 2002). Copolymer samples

exhibited blue emission in dichloromethane with a 70% quantum yield.

Kim et al. developed a 9,9’-dioctylfluorene anchored aromatic

polyoxadiazole scaffold 20 through a Suzuki coupling reaction (Kim et al.

2006). The authors prepared the monomer unit (oxadiazole) (51%) while mixing

5-bromo-2-hydroxybenzoic acid in the presence of polyphosphoric acid (PPA). The

oxadiazole moiety in the polymer was guarded by the bis(hydroxyphenyl) group in

its 2-position (Scheme 19). The tert-butoxycarbonyl group was utilized to protect the

highly vulnerable hydroxyl group before polymerization and subsequently eliminated

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