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Review
. 2023 Mar 12;24(6):5406.
doi: 10.3390/ijms24065406.

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Sergey V Baykov  1 , Anton A Shetnev  2 , Artem V Semenov  1 , Svetlana O Baykova  1 , Vadim P Boyarskiy  1
Affiliations
Review

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

Sergey V Baykov et al. Int J Mol Sci. .

Abstract

1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of O-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work-up. However, it requires the preparation and isolation of O-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds.

Keywords: 1,2,4-oxadiazole; amidoximes; base catalyzed cyclization; bioactive compounds; bioisosteres; oxidative cyclization; room temperature.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Room-temperature cyclization of O–acylamidoximes under TBAF catalysis.
Scheme 2
Scheme 2
Mechanism of TBAF-catalyzed synthesis of 1,2,4-oxadiazoles.
Scheme 3
Scheme 3
Synthesis of carbamoyloxadiazoles under TBAF catalysis.
Scheme 4
Scheme 4
Synthesis of sterically hindered 3-(1,2,4-oxadiazol-3-yl)pyridines under TBAF catalysis.
Scheme 5
Scheme 5
N-Boc-α-methyl-β-alanine-N-carboxyanhydride as an acylating agent.
Scheme 6
Scheme 6
Sensing of fluoride based on the O-acylamidoxime cyclocondensation.
Scheme 7
Scheme 7
Synthesis of glycosylated 1,2,4-oxadiazole via TBAF-catalyzed cyclization.
Scheme 8
Scheme 8
TBAH-catalyzed O-acylamidoxime cyclization.
Scheme 9
Scheme 9
Preparation of various 1,2,4-oxadiazol-furoxan hybrids.
Scheme 10
Scheme 10
Cyclization of O–acylamidoximes into 1,2,4-oxadiazoles in KOH/DMSO medium.
Scheme 11
Scheme 11
Cyclization of O–acylamidoximes with double bond in KOH/DMSO medium.
Scheme 12
Scheme 12
Synthesis of 1,2,4-oxadiazolones bearing nitro-groups.
Scheme 13
Scheme 13
Cyclization of O-acylamidoximes into bioactive 1,2,4-oxadiazoles in KOH/DMSO medium [91,92,93].
Scheme 14
Scheme 14
Reaction of amidoximes with esters in NaOH/DMSO medium.
Scheme 15
Scheme 15
Preparation of bioactive 1,2,4-oxadiazoles from esters and amidoximes [106,109,110].
Scheme 16
Scheme 16
Synthesis of anti-inflammation agents based on the 1,2,4-oxadiazol-3-yl)piperazine scaffold.
Scheme 17
Scheme 17
Synthesis of 1,2,4-oxadiazin-5(6H)-ones from amidoximes and maleic dimethyl ester.
Scheme 18
Scheme 18
Reaction of amidoximes and carboxylic acids in NaOH/DMSO medium.
Scheme 19
Scheme 19
Reaction of amidoximes with acyl chlorides in NaOH/DMSO medium.
Scheme 20
Scheme 20
Reaction of amidoximes with dicarboxylic acid anhydrides in NaOH/DMSO medium.
Scheme 21
Scheme 21
Synthesis of cycloalkyl carboxylic acids bearing 1,2,4-oxadiazole moiety.
Scheme 22
Scheme 22
Synthesis of 1,2,4-oxadiazole substituted acrylic acids.
Scheme 23
Scheme 23
Synthesis of 2-(1,2,4-oxadiazol-5-yl)anilines.
Scheme 24
Scheme 24
Reaction of amidoximes with aldehydes in NaOH/DMSO medium.
Scheme 25
Scheme 25
Synthesis of 1,2,4-oxadiazoles in aprotic solvents other than DMSO: in NaOH/DMF medium (A); in KOH/DMF medium (B); in KOH/DMA medium (C).
Scheme 26
Scheme 26
Copper-catalyzed cascade oxidative reaction of amidines and methylarenes.
Scheme 27
Scheme 27
Mechanism of the copper-catalyzed oxidative process.
Scheme 28
Scheme 28
Oxidative cycloaddition of aldoximes with nitriles catalyzed by hypervalent iodine reagent.
Scheme 29
Scheme 29
Synthesis of orally bioavailable cyclohexanol-based NR2B-selective NMDA receptor antagonists with analgesic activity.
Scheme 30
Scheme 30
Synthesis of alkyl3-(3-aryl-1,2,4-oxadiazol-5-yl)propanoates (AAOPs) by reaction of aldoximes with NCS.
Scheme 31
Scheme 31
Synthesis of 3-amino-1,2,4-oxadiazoles from aromatic N-acylguanidines.
Scheme 32
Scheme 32
Mechanism of N–O oxadiazole bond oxidative formation with PIDA.
Scheme 33
Scheme 33
NBS-promoted oxidative cyclization of N-acyl amidines.
Scheme 34
Scheme 34
Oxidative cyclization of N-benzyl amidoximes.
Scheme 35
Scheme 35
Cyclization of N-benzyl amidoximes by the electro-oxidation method.
Scheme 36
Scheme 36
Synthesis of 5-(1,2,4-oxadiazol-5-yl)pyrimidine-2,4(1H,3H)-dienes and diethyl (1,2,4-oxadiazol-5-yl)phosphonates via 1,3-dipolar cycloadditions.
Scheme 37
Scheme 37
Synthesis of 1,2,4-oxadiazoles by cyclization of substituted N’-((3-oxoprop-1-en-1-yl)oxy)benzimidamides.
Scheme 38
Scheme 38
Metal-catalyzed [2+3]-cycloaddition of silyl nitronate and chloroacetonitrile.
Scheme 39
Scheme 39
Synthesis of 3,5-disubstituted-1,2,4-oxadiazoles from nitroalkenes, arenes, and nitriles under the superelectrophilic activation.
Scheme 40
Scheme 40
Synthesis of 3-(5-nitro-2H-tetrazol-2-yl)substituted-1,2,4-oxadiazoles.
Scheme 41
Scheme 41
Synthesis of 2-(1,2,4-oxadiazol-3-yl)propan-2-amine and and its deuterated analog.
Scheme 42
Scheme 42
Sc(OTf)3-catalyzed condensation of amidoximes with orthoester.
Scheme 43
Scheme 43
Synthesis of 3-aryl-5-(trifluoromethyl)-1,2,4-oxadiazoles.
Scheme 44
Scheme 44
O-acylamidoxime cyclocondensation to 1,2,4-oxadiaozle using Vilsmeier reagent.
Scheme 45
Scheme 45
Synthesis of anticancer agents bearing 1,2,4-oxadiazole moiety using Vilsmeier reagent [149,150,151,152].
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