Product Class 6 - 1,2,4-Oxadiazoles-Science of Synthesis, 2004 13-6, 127-184

Science of Synthesis classification: 13.
General Introduction
Previously published information regarding this product subclass can be found in HoubenWeyl, Vol.E 8c, pp409413.
Comprehensive reviews appeared in 1962,[ 1 , 2 ] 1965,[ 3 ] 1976,[ 4 ] 1984,[ 5 ] and 1996,[ 6 ] and include detailed listings of
known 1,2,4-oxadiazoles. Substituted 1,2,4-oxadiazoles were first reported in the literature in the 1880s, [ 7 12 ] although the
synthesis of the unstable unsubstituted parent compound was not reported until 1962. [ 13 ]
The 1,2,4-oxadiazole ring is planar, and the bond lengths are consistent with the possession of some aromatic character;
[ 6 ]
the N2C3 and N4C5 bonds also show significant double-bond character. A full discussion of X-ray diffraction
analyses and other spectroscopic characteristics such as NMR spectra, [ 14 ] mass spectra, ultraviolet spectra, and IR spectra is
available.[ 6 ] In relation to tautomeric structural considerations, the position of the equilibrium among the tautomers of 3hydroxy- and 5-hydroxy-substituted derivatives is not the same. For example, [ 4 , 15 , 16 ] in the 5-hydroxy compound 1 , the oxo
forms ( 2 and 3 ) seem to predominate, whereas in the 3-hydroxy compound 4 , the hydroxy form predominates
( Scheme 1 ). This is because the electronegative ring oxygen in the 5-hydroxy compound can maintain a carbonyl adjacent
to it, a situation that is not possible in the 3-hydroxy compound. [ 4 , 17 ] Note that the nature of the solvent is crucial in
determining the preferred tautomeric form of such heterocycles. Thus, in chloroform and in the solid state,
[ 18 , 19 ]
structures 5 and 6predominate; however, in ethanol, acetone, or dimethyl sulfoxide, the enol 4 allows efficient
hydrogen-bond formation, and this is the preferred form. In 1,2,4-oxadiazolamines, the situation is greatly simplified, as the
tautomeric imine 8 ( Scheme 2 ) is much less basic than the amine form 7 , which predominates.[ 4 , 6 , 15 , 16 ]
Scheme 1 Tautomerism
of 1,2,4-Oxadiazolols
1,2,4-Oxadiazolamines
[ 4 , 15 , 16 ]
Scheme 2 Tautomerism in
[ 4 , 6 , 15 , 16 ]
Whereas disubstituted 1,2,4-oxadiazoles are thermally quite stable, monosubstituted and unsubstituted systems are
considerably less stable. Thus, 3,5-diphenyl-1,2,4-oxadiazole can be distilled at 296C without decomposition, [ 6 , 7 ] whereas
3-phenyl-1,2,4-oxadiazole decomposes rapidly at 200C. The thermal reactions of N-aryl-3-phenyl-1,2,4-oxadiazol-5amines have been investigated recently. [ 20 ] Disubstituted 1,2,4-oxadiazoles can withstand boiling aqueous sodium hydroxide
or hydrochloric acid, whereas monosubstituted systems readily undergo hydrolysis under such conditions. [ 4 6 ] 1,2,4Oxadiazoles show a very low reactivity towards electrophilic attack at carbon, the only known example being electrophilic
mercuration of the 5-unsubstituted systems.[ 21 ] Several 3-aryl-5-methyl-1,2,4-oxadiazoles can serve as ligands for transitionmetal complexes, proving that electrophilic attack at nitrogen is possible. [ 13 , 22 , 23 ] Nucleophilic displacement of C5
substituents such as 5-chloro, 5-bromo, 5-alkoxy, 5-(arylsulfanyl), and 5-(trichloromethyl) is an important mode of reaction.
Conversely, the 3-substituted systems are not so reactive, and show a lower tendency to be displaced. [ 3 6 ]Reductions of
1,2,4-oxadiazoles, either with metal hydrides or by catalytic hydrogenation, result in cleavage of the ON bond, with the
potential for further reactions of the resulting amino carbonyl moieties. [ 3 6 ]
1,2,4-Oxadiazoles have attracted much interest in the literature as bioisosteres for esters and amides, [ 24 26 ]and they exhibit a
wide range of biological activity as dipeptidomimetics, [ 26 ] highly potent muscarinic agonists,[27 ] benzodiazepine receptor
antagonists,[ 28 , 29 ] antirhinovirals,[ 30 ] antitussives,[ 31 , 32 ] anthelmintics,[ 33 , 34] inhibitors of the tyrosine kinase ZAP-70,
[ 35 ]
nonpeptidic angiotensin-II receptor antagonists, [ 36 ] and selective histamine H3 receptor antagonists;[ 37 ] they also show a
variety of other physiological activities. [ 4 6 ] Several patents have described the use of 1,2,4-oxadiazoles as plant-protection
agents.[ 38 , 39 ] Other uses[ 6 ] include as constituents of fluorescence whiteners, [ 40 ] 1,2,4-oxadiazole polymers in the
manufacture of graphite,[ 41 ] and polymeric systems as fuel-tank sealants.[ 42 ] The liquid-crystal properties of 1,2,4oxadiazoles have also been investigated. [ 43 ]
There are no general patterns of toxicity associated with 1,2,4-oxadiazoles as a class; however, it is important to emphasize
that good laboratory practice and good manufacturing practice protocols should always be employed during handling and
manipulation of these compounds. Several specific types of 1,2,4-oxadiazole have potent physiological and biological
activity, [ 24 37 ] for example, as highly potent muscarinic agonists.[ 6 , 27 ]
13.6.1 Synthesis by Ring-Closure Reactions
13.6.1.1 By Formation of One OC and One NC Bond

13.6.1.1.1 Fragments ONC and NC
13.6.1.1.1.1
Method 1: By the 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides with Nitriles
Introductory Text
This is one of the major methods used to access 1,2,4-oxadiazoles 9 and, as such, has received much attention in the
literature, and has been reviewed extensively. [ 1 6 ] Table 1 shows a typical selection of the 1,2,4-oxadiazoles that are
available by this route. The nitrile oxides 10 can be generated from a nitroalkane and phenyl isocyanate (the Mukaiyama
Hoshino method; Scheme 3 ),[ 44 , 45 ] via the dehydrodehalogenation of imidoyl halides ( Scheme 4 ),[ 44 48 ] and by a variety
of other, less common, methods.[ 6 , 49 , 50 ] 1,3,5-Triazine has been used as a synthetic equivalent of hydrogen cyanide.
[ 51 ]
Halogen,[ 52 ] trifluoromethyl,[ 53 ] aroyl,[ 54 , 55 ]and a variety of other substituents[ 4 6 ] on the nitrile oxide have been
employed. Aryl-substituted nitriles are most commonly employed as the dipolarophile, [ 6 , 47 , 48 ] but the relatively unreactive
aliphatic nitriles will react in the presence of Lewis acids. [ 56 ] Heterocyclic -enaminonitriles,[ 57 , 58 ] cyanates and related
species,[ 59 ] and a series of N-cyano compounds[ 6 ] can also function as the dipolarophile.
Table 1 1,2,4-Oxadiazoles by Cycloaddition of Nitrile Oxides to Nitriles[ 47 , 52 55 , 59 ]

13.6.1.1.1.1.1
Variation 1: By Using an Aliphatic Nitrile Oxide Generated from a Nitroalkane and Phenyl
Isocyanate
Intoductory Text
In the presence of a tertiary amine and phenyl isocyanate, enolizable nitroalkanes give nitrile oxides 10 that undergo in situ
cycloaddition with nitriles to give 1,2,4-oxadiazoles 9 ( Scheme 3 ).[ 44 , 45 , 59 , 60 ]
Scheme 3 1,2,4-Oxadiazoles by the MukaiyamaHoshino

Method
[ 44 , 45 , 59, 60 ]
Experimental Procedure
3-Methyl-5-[(4-nitrophenyl)sulfanyl]-1,2,4-oxadiazole ( 9 , R1=Me; R2=4-O2NC6H4S); Typical Procedure:[ 59 ]
A soln of 4-nitrophenyl thiocyanate (1.80g, 10mmol) and PhNCO (3.57g, 30mmol) in toluene (20mL) was added
dropwise to a soln of EtNO2 (1.13g, 15mmol) and Et3N (0.5mL) in toluene (20mL). The mixture was stirred for 16h, and
the precipitated diphenylurea was removed by filtration. The filtrate was concentrated and chromatographed (silica gel,
hexane/EtOAc); yield: 1.14g (48%); mp 143145C.
13.6.1.1.1.1.2
Variation 2: By Using Nitrile Oxides Generated from Imidoyl Halides (Halooximes)
Introductory Text
Imidoyl halides (halooximes) 11 are available through halogenation of oximes, [ 44 46 , 51 59 , 61 , 62 ] and yield nitrile
oxides 10 upon treatment with base, or sometimes upon simple heating ( Scheme 4 ). The base used is often triethylamine,
[ 44 , 45 , 59 ]
but it can be sodium hydrogen carbonate. The in situ cycloaddition of the nitrile oxide to a nitrile gives the 1,2,4-
oxadiazole 9 .[ 47 , 48 ] This is a very widely used method,[ 44 48 , 51 59 , 62 ]and is noteworthy as it allows access to 5-unsubstituted
systems[ 51 ] and 3-bromo systems. The latter are useful as precursors for further substitution reactions. [ 52 ]
Scheme 4 1,2,4-Oxadiazoles from Imidoyl Halides and

Nitriles
[ 44 48 , 51 59 , 62 ]
Ethyl 3-Bromo-1,2,4-oxadiazole-5-carboxylate ( 9 , R1=Br; R2=CO2Et); Typical Procedure:[52 ]
The dibromo aldoxime 11 (R1=X=Br; 6.0g, 30mmol) was added in small portions over 45min to a stirred soln of ethyl
cyanoformate (5.9g, 60mmol) in toluene (10mL) containing NaHCO 3 (8.0g, 95mmol) in suspension at 90C. The mixture
was stirred at 90C for 3h, diluted with EtOAc (80mL), and poured into H 2O (100mL). The organic layer was separated,
washed with H2O, and dried (Na2SO4). The soln was evaporated and the residue was purified by chromatography (silica gel,
hexane/EtOAc) to give an oil; yield: 5.3g (80%); bp 80C/0.5Torr.
13.6.1.1.1.2
Method 2: By 1,3-Dipolar Cycloaddition of Nitrile Oxides to Imines, Followed by Aromatization of

the Intermediate 4,5-Dihydro-1,2,4-oxadiazole
Introductory Text
The reaction of a nitrile oxide 10 with a C=N bond to give a dihydro-1,2,4-oxadiazole 12 , which then undergoes
spontaneous or forced aromatization or oxidation (loss of XY) to form the 1,2,4-oxadiazoles 9 , offers a further 1,3-dipolar
approach ( Scheme 5 ).[ 44 , 45 , 63 70 ] The range of carbonnitrogen functionalities that react in such a manner includes
guanidine,[ 64 ] 1-azetines,[ 65 ] imidates,[ 66 ] amidines,[ 67 ] and certain 2-pyrazolines;[70 ] some examples are given in Scheme 5 .
Scheme 5 1,3-Dipolar Cycloadditions to Imines, with

Aromatization
Tabelle anzeigen / Show table
[ 44 , 45 ,64 70 ]
4-(5-Amino-1,2,4-oxadiazol-3-yl)-2,6-di-tert-butylphenol [ 9 , R1=4-HO-3,5-(t-Bu)2C6H2; R2=NH2]; Typical
Procedure:[ 64 ]
A soln of 3,5-di-tert-butyl-4-dihydroxybenzenecarboximidoyl chloride (6.2g, 22mmol) in abs EtOH was added dropwise to
a soln of guanidine (2.6g, 44mmol) in EtOH (100mL). The mixture was stirred at rt for 18h and then evaporated. The
residual oil was partitioned between EtOAc (125mL) and H 2O (125mL), and the mixture was acidified to pH 45 with 0.1
M aq HCl. The organic layer was separated, washed with H 2O, dried (MgSO4), and evaporated to give the crude material (5
g), which was purified by flash chromatography (hexane/EtOAc); yield: 1.0g (16%); mp 202204C.
13.6.1.1.2 Fragments CNC and NO

13.6.1.1.2.1
Method 1: Via N-Acylamidoximes
Introductory Text
N-Acylamidoximes 14 cyclize to give 1,2,4-oxadiazoles 9 ( Scheme 6 ).[ 4 , 6 , 71 ] Competing Beckmann rearrangement of
the N-acylamidoxime can be a problem.[ 72 ] N-Acylamidoximes are usually nonisolable intermediates that cyclize
spontaneously at room temperature. They are, therefore, generated in situ from N-acylimidic chlorides ( 13 , X=Cl),
[ 73 ]
acylamidines ( 13 , X=NR3 2)[ 74 ] (generated in turn from the reaction of amides with N,N-dialkylformamide dialkyl
acetals[ 74 , 75 ]), N-acyl(alkylsulfanyl)imides ( 13 , X=SR3),[ 17 ] N-acyl(alkoxy)imides ( 13 , X=OR3),[ 76 ] and a variety of
similar precursors.[ 4 6 ] The wide range of readily available precursors make this a popular route to the 1,2,4-oxadiazole
nucleus. Note that N-acylamidoximes cannot be prepared by the acylation of amidoximes because O-acylation occurs more
rapidly.[ 4 6 ] N-Acylamidoximes are often formed as intermediates during the synthesis of 1,2,4-oxadiazoles from other
heterocycles[ 5 , 6 ] (see Section 13.6.2).
Scheme 6 In Situ Formation of N-Acylamidoximes
[ 17 , 73 76 ]
13.6.1.1.2.1.1
Variation 1: Via N-Acylamidoximes Derived from the Reaction of Amide Precursors

with N,N-Dialkylformamide Dialkyl Acetals
Introductory Text
Treatment of the acylamidines 16 with hydroxylamine gives the N-acylamidoximes 14 , which undergo in situ cyclization to
give the 1,2,4-oxadiazoles 9 ( Scheme 7 ). The ready availability of acylamidines from the reaction of amides with N(dimethoxymethyl)-N,N-dimethylamine ( 15 , R1=H) makes this an excellent method for the generation of 5monosubstituted 1,2,4-oxadiazoles. [ 74 , 75 ] The use of substituted acetals, e.g. 15 (R1=Me), gives access to 3,5-disubstituted
1,2,4-oxadiazoles.[ 75 ]
Scheme 7 1,2,4-Oxadiazoles from Acylamidines and

Hydroxylamine
[ 74 , 75 ]
5-(3,5-Dimethoxyphenyl)-1,2,4-oxadiazole [ 9 , R1=H; R2=3,5-(MeO)2C6H3]; Typical Procedure:[ 74 ]
A soln of 3,5-dimethoxybenzamide (71.8g, 396mmol) in the acetal 15 (R1=H) was stirred at 120C for 1.5h, while the
MeOH that formed was collected through a reflux condenser. Upon cooling, N-[(dimethylamino)methylene]-3,5dimethoxybenzamide was deposited as colorless crystals; yield: 91.7g (94%); mp 108110C.
Next, the freshly prepared N-[(dimethylamino)methylene]-3,5-dimethoxybenzamide (10.0g, 42.4mmol) was added to a soln
of NH2OHHCl (3.54g, 51.3mmol) in a mixture of 5M aq NaOH (10.2mL, 51.0mmol) and 70% aq AcOH (50mL). The
mixture was stirred at rt for 10min, and then diluted with H 2O (30mL). The mixture was cooled in an ice bath for 1h, and
the colorless crystals were removed by filtration, washed with H 2O, and dried; yield: 6.20g (71%); mp 108109C.
13.6.1.1.2.1.2
Variation 2: Via N-Acylamidoximes Derived from Nitriles
Introductory Text
Treatment of the N-acyl(alkoxy)imides (also known as N-acyl imino ethers or N-acylimidates) 18 with hydroxylamine also
gives the N-acylamidoximes 14 , which undergo cyclization in situ to give the 1,2,4-oxadiazoles 9 ( Scheme 8 ).
[ 76 , 77 ]
Nitriles are excellent templates for the easy, in situ, generation of the requisite N-acyl(alkoxy)imides 18 .[ 6 , 76 , 77 ] Thus,
treatment of a nitrile with acidic methanol gives an imidate (imino ether) 17 that reacts with acid chlorides to give the
corresponding N-acyl(alkoxy)imide 18 .[ 77 ] The use of chloroformates instead of acid chlorides ( Scheme 8 ; R2=OMe)
results in a loss of methanol rather than water from the intermediate 14 , and gives the 5-hydroxy/5-oxo derivative ( 9 , R2=
OH).[ 77 ]
Scheme 8 Synthesis from N-Acyl(alkoxy)imides and

Hydroxylamine
[ 76 , 77 ]
1,2,4-Oxadiazoles 9 from N-Acyl(alkoxy)imides and Hydroxylamine; General Procedure:[ 77 ]
An acid chloride (0.1mmol) in dry toluene (20mL) was added dropwise over 30min to an ice-cold, stirred solution of the
imidate[ 77 ] 17 (0.1mmol) and Et3N (0.11mmol) in dry toluene (200mL). Stirring was maintained at rt for 12h, then the
precipitate was filtered off and washed with toluene (25mL). The combined filtrates were evaporated, and the residue was
distilled under reduced pressure to give the corresponding N-acyl(alkoxy)imide (18 , R3=Et).
A mixture of NaOMe (0.59g, 11mmol) and NH2OH (0.36g, 11mmol) in dry MeOH (50mL) was stirred for 15min. The Nacyl(alkoxy)imide ( 18 , R3=Et) (10mmol) was added, and the mixture was stirred for 12h at rt (18 , R3=Et; R1R2=Ph,
Me), or for 6h at the reflux temperature ( 18 , R3=Et; R1R2=Ph, 4-ClC6H4). The mixture was evaporated and the residue
was washed with H2O, and recrystallized to yield 1,2,4-oxadiazoles 9 .
13.6.1.1.2.1.3
Variation 3: Via N-Acylamidoximes Derived from N-Acyl Isothiocyanates
Introductory Text
N-Acyl isothiocyanates 19 are valuable precursors for the generation of N-acylamidoximes.[ 78 ] Treatment of the
isothiocyanate with an alcohol[ 78 ] or an aryl Grignard reagent[ 78 ] leads to the N-acylthioamides ( 20 , R1=OEt, Ar1), which
give the corresponding 1,2,4-oxadiazoles 9 (R1=OEt, Ar1; R2=Ph) via the N-acylamidoxime 14 on treatment with
hydroxylamine,[ 78 , 79 ] ( Scheme 9 ). 5-Substituted 3-[(hydroxyimino)benzyl]-1,2,4-oxadiazoles 9 [R1=PhC(=NOH)CH2; R2
=Me, Ph] are also available by using a similar methodology. [ 79 ]
Scheme 9 Reaction of N-Acylthioamides with

Hydroxylamine
[ 78 , 79 ]
3-Ethoxy-5-phenyl-1,2,4-oxadiazole ( 9 , R1=OEt; R2=Ph); Typical Procedure:[ 78 ]
A mixture of O-ethyl benzoylthiocarbamate[ 78 ] ( 20 , R1=OEt; R2=Ph; 2.1g, 10mmol) and NH2OHHCl (1.4g, 2.0mmol)
in pyridine (10mL) was refluxed for 16h. The mixture was cooled and H 2O was added. The resulting solid was removed by
filtration and recrystallized (aq EtOH); yield: 0.92g (46%); mp 46.547.5C.
13.6.1.1.2.1.4
Variation 4: Via N-Acylamidoximes Derived from N-Cyano Compounds
Introductory Text
The reaction of acylcyanamides, e.g. 21 ,[ 80 ] or their acetal derivatives, [ 81 83 ] with hydroxylamine is an important route to
1,2,4-oxadiazolamines, e.g. 23 , and possibly proceeds via the corresponding N-acylamidoxime, e.g. 22 ( Scheme 10 ). The
exact nature of the intermediate and the regiochemical outcome of the reaction in general terms are matters of debate, and
seem to be highly dependent on the substrate. [ 80 83 ]Cautious assignment of the positional isomerism of the structure is
therefore recommended. This reaction is not widely applicable, but it does allow access to important 1,2,4-oxadiazolamines.
[ 64 , 80 83 ]
Scheme 10 Synthesis of 1,2,4-Oxadiazolamines from

Acylcyanamides
[ 80 83 ]
5-(2,6-Dichlorobenzyl)-1,2,4-oxadiazol-3-amine ( 23 ); Typical Procedure:[ 80 ]
2,6-Dichlorophenylacetyl chloride (13.38g, 60mmol) in acetone (50mL) was added slowly at 1015C to a soln of
cyanamide (2.64g, 63mmol) in H2O (50mL) adjusted to pH 12 with 40% aq NaOH. The pH was maintained at 12 by
occasional addition of 40% aq NaOH. On completion of the addition, the mixture was stirred for up to 1h to ensure that no
acid chloride remained. The mixture was filtered to give a small amount of residue, and the filtrate was acidified to pH 2
with dil HCl. The resulting crystals of the acylcyanamide 21 were filtered, washed well with H 2O, dried, and dissolved in
EtOH (125mL) containing NH2OHHCl (6.72g, 97mmol) and pyridine (25mL). The mixture was stirred at rt overnight,
and the crystalline product was collected by filtration, washed with EtOH and Et 2O, and dried; yield: 9.65g (66%); mp 182
185C.
13.6.1.1.2.2
Method 2: By Nitrosation of N-Acyl -Amino Acid Derivatives Bearing Active Hydrogens on a

Carbon Atom
Introductory Text
Nitrosation of N-acyl -amino acid derivatives 24 gives 1,2,4-oxadiazoles ( Scheme 11 ).[ 6 , 72 , 84 88 ] This method has
received a reasonable amount of attention in the literature, because of the ready availability of the substrates 24 , particularly
from -amino acids. Interestingly, N-substituted amides do not react, and there is strong evidence that the reaction proceeds
by an initial N-nitrosation,[ 6 , 72 ] followed by rearrangement to the C-nitroso species. In the example shown, nitrosation of the
acylated -amino acids 24 (X=OH) gives the 1,2,4-oxadiazoles 9 through an initial N-nitrosation followed by Cisomerization.[ 72 ]
Scheme 11 Nitrosation of N-Acyl -Amino Acid

Derivatives
[ 6 , 72 , 84 88 ]
3-Isobutyl-5-methyl-1,2,4-oxadiazole ( 9 , R1=iBu; R2=Me); Typical Procedure:[ 72 ]
CAUTION: Many N-nitroso compounds are carcinogens.
An N-acyl -amino acid 24 (X=OH) was treated with N2O4/anhyd NaOAc in CH2Cl2 at 70C, or with NOBF4 in MeCN at
0C. The residue was extracted with Et 2O, and the ethereal soln was washed with 1% aq NaHCO 3 and H2O. Evaporation of
the Et2O gave the corresponding N-nitroso compound which was used directly.
For example, a soln of N-acetyl-N-nitroso-D-leucine (2.33g, 11.5mmol) and Et3N (2.2g, 22mmol) in MeCN (230mL) was
irradiated for 1.25h with a 200-W, medium-pressure Hg lamp (Hanovia 654A36) with a circulating filter soln of sodium
hydrogen phthalate/NaNO2, and a cooling bath to hold the temperature at 20C. The N-nitroso compound was added, the
solvent was distilled through a Widmer column, and the residue was diluted with H 2O. The aqueous soln was made basic by
adding aq Na2CO3, and extracted with Et2O to give a neutral fraction that on preparative GC gave a volatile oil; yield: 1.1g
(68%).
13.6.1.1.3 Fragments ONCN and C

13.6.1.1.3.1
Method 1: From an Amidoxime and a Carbonic Acid Derivative
Introductory Text
The reaction between an amidoxime 25 and a single carbon unit at its highest oxidation level leads ultimately to the 1,2,4oxadiazol-5-ones 27 ( Scheme 12 ), which are tautomers of the 5-hydroxy system 28 [ 15 19 ] (see Section 13.6 , General
Introduction, for a discussion of tautomerism). The process has been well investigated. [ 6 ,30 , 64 , 89 93 ] Chloroformates,
[ 30 , 64 , 92 ]
carbamoyl halides,[ 89 ] phosgene,[ 90 ] triphosgene,[ 93 ] and thiophosgene,[ 91 ] all undergo the reaction. Thiophosgene
gives the 5-thioxo system. Some typical examples are shown in Scheme 12 . The reaction often proceeds through an
intermediate O-acyl amidoxime 26 .
Scheme 12 1,2,4-Oxadiazoles from Carbonic Acid

Derivatives
[ 6 , 30 , 64 , 89 93 ]
13.6.1.1.3.1.1
Variation 1: From an Amidoxime and a Chloroformate
Introductory Text
This procedure has been used to synthesize 1,2,4-oxadiazoles for investigations on novel dual 5-lipoxygenase and
cyclooxygenase inhibitors,[ 64 ] and in the study of 1,2,4-oxadiazoles as ester bioisosteric replacements with antirhinovirus
activity. [ 30 ] The practical methodology used with chloroformates tends to be identical to that used for acid chlorides, and the
procedure below is, therefore, rather typical (see also Section 13.6.1.1.3.2.4).
3-{3,5-Dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl}-1,2,4-oxadiazol-5(4H)-one {27 , R1=3,5Dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl}; Typical Procedure: [ 30 ]
A soln of ethyl chloroformate (1.05mL, 11.0mmol) in acetone (6mL) was added to a chilled suspension of the
amidoxime 25 {R1=3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl; 3.03g, 10.0mmol}, dry acetone (30mL),
and finely divided K2CO3 (1.1 equiv). The mixture was stirred at 0C for 1h, diluted with H 2O (100mL), and extracted with
CH2Cl2 (325mL). The combined organic extracts were washed with brine, dried, filtered through a short column of
Florisil, and concentrated in vacuo to give the crude O-acyl amidoxime 26 . This crude solid was heated at 120130C for 5
60min to give the crude 1,2,4-oxadiazole, which was recrystallized (MeOH) to give white needles; yield: 2.38g (72%); mp
194195C.
13.6.1.1.3.1.2
Variation 2: From an Amidoxime and Phosgene
Introductory Text
Phosgene,[ 90 ] triphosgene,[ 93 ] or thiophosgene[ 91 ] can all be used to great effect. In the example below, phosgene reacts with
acetamidoxime 25 (R1=CF2NF2) to give the fluorinated 1,2,4-oxadiazol-5(4H)-one 27 (R1=CF2NF2). The procedure is
typical of reactions involving phosgene.
3-[(Difluoroamino)(difluoro)methyl]-1,2,4-oxadiazol-5(4H)-one ( 27 , R1=CF2NF2); Typical Procedure:[ 90 ]
CAUTION: Phosgene is a severe respiratory irritant and very toxic by inhalation.
A large excess of COCl2 was condensed in a soln of the amidoxime 25 (R1=CF2NF2; 0.081g, 0.5mmol) in Et2O at 196C.
The temperature was raised slowly and held at 20C for 30min, and then raised to 25C with shaking. The solvent was
removed under vacuum to leave the intermediate chloroformate 26 [R1=CF2NF2, X(Y)=Cl]; yield: quant.
This intermediate was heated at 120C for 4h under vacuum to give the corresponding 1,2,4-oxadiazol-5(4H)-one; yield:
quant.
13.6.1.1.3.2
Method 2: From an Amidoxime and a Carboxylic Acid or a Carboxylic Acid Derivative
Introductory Text
Condensation of an amidoxime 25 with a carboxylic acid derivative gives an O-acyl amidoxime 29 that on heating,
undergoes cyclization to form the 1,2,4-oxadiazole nucleus ( Scheme 13 ). This is the classic synthesis first reported by
Tiemann and Krger.[ 7 ]
Scheme 13 Synthesis of 1,2,4-Oxadiazoles from

Amidoximes
[ 7 , 25 , 94 ]
The amidoximes 25 necessary for this reaction are easily obtained by the reaction of nitriles with hydroxylamine, [25 , 30 , 95 ] or
by the chlorination of an oxime followed by reaction with ammonia ( Scheme 14 ).[ 3 , 44 , 45 , 61 ]Significantly, the reaction of
nitriles with hydroxylamine and the subsequent synthesis of 1,2,4-oxadiazoles has been accomplished in the solid phase (see
Section 13.6.5.2).
Scheme 14 Synthesis of
Amidoximes
[ 3 , 25 , 30 , 44 , 45 , 61 , 95 ]
Many modern variations of this approach to 1,2,4-oxadiazoles incorporate the in situ generation of the intermediate O-acyl
amidoxime 29 , which then cyclizes spontaneously. [ 25 , 94 ] All of the common carboxylic acid derivatives can be used as the
single-carbon unit that reacts with the amidoxime NCNO unit, [ 1 6 ]and the use of the parent carboxylic acids (usually
after activation with peptide-coupling reagents) is well established. [ 24 , 25 , 96 ] Together, these methods provide the most
versatile and powerful tools available for the synthesis of 1,2,4-oxadiazoles. The emergence of the 1,2,4-oxadiazoles as ester
and amide bioisosteres[ 24 26 ,35 , 97 ] has played a major part in the popularity of these synthetic routes, and thus the synthesis of
1,2,4-oxadiazoles from esters[ 27 , 28 , 98 ] has proved to be useful. The use of amides is practical in terms of the separation and
recovery of the product, but the approach lacks general applicability. [ 99 ] By far the most popular, versatile, and generally
applicable starting materials for reaction with the amidoxime are the carboxylic acids themselves, acid halides, and acid
anhydrides. The acid anhydride method suffers the potential disadvantage of the loss of half of the carboxylic acid precursor,
although this is not usually a problem with simple anhydrides. Both the acid halide and acid anhydride routes have proved to
be incompatible with complex functionalities, [ 24 ,30 ] and are particularly unsuited to scale-up in the common variation where
boiling pyridine is used to effect the in situ cyclization. However, the two approaches work well with simple substrates, and
both retain their popularity. The use of carboxylic acids as the one-carbon component, under activation from peptidecoupling reagents, has become increasingly common, and offers several advantages over other methods. [ 24 , 25 , 96 ]These
advantages include the ready availability of carboxylic acids; the avoidance of pyridine in the cyclization step; and an
increased range of compatible functionalities, including chiral, nonracemic groups. [ 24 ]
13.6.1.1.3.2.1
Variation 1: From an Amidoxime and a Carboxylic Acid
Introductory Text
The direct treatment of amidoximes with a carboxylic acid is unreliable and often yields mixtures of 1,2,4-oxadiazoles
(e.g., Scheme 15 ).[ 6 ]
Scheme 15 Direct Reaction of an Amidoxime with a

Carboxylic Acid
[ 6 ]
A range of peptide-coupling reagents is known to effect the conversion of a variety of carboxylic acids cleanly into 1,2,4oxadiazoles upon treatment with an amidoxime ( Table 2 ). Dicyclohexylcarbodiimide (DCC) enjoyed early success in this
respect.[ 96 ] More recently,[ 24 , 35 ] N-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC); bis(2-oxo-1,3oxazolidin-3-yl)phosphinic dichloride (BOP-Cl) and 1,1-carbonyldiimidazole (CDI), as well as dicyclohexylcarbodiimide,
have proved to be successful under neutral conditions in diglyme, initially at 50C to form the O-acyl amidoxime, followed
by heating to 100C in the same solvent to effect cyclization. An improved method employing 1,1-carbonyldiimidazole in
dimethylformamide as solvent, first at rt and then at 115C, affords a clean one-pot approach, which is applicable to parallel
solution-phase synthesis.[ 25 ]This latter methodology has been adapted to allow the solid-phase synthesis of 1,2,4-oxadiazoles
under a variety of conditions, (see Sections 13.6.5.1 and 13.6.5.2). Table 2 shows a selection of the 1,2,4-oxadiazoles that
are available from the various solution-phase methods.
Table 2 Synthesis of 1,2,4-Oxadiazoles from Carboxylic Acids and Amidoximes by Using

Peptide-Coupling Reagents[ 24 , 25 ]
5-Propyl-3-(4-tolyl)-1,2,4-oxadiazole ( 9 , R1=4-Tol; R2=Pr); Typical Procedure:[ 24 ]
The amidoxime 25 (R1=4-Tol; 0.15g, 1.0mmol) was treated with butanoic acid (1.0mmol) in the presence of EDC (0.38g,
2.0mmol) in diglyme (23mL) at 50C under N2 overnight. The mixture was then heated at 110C under N2 for 3h to effect
cyclization. The solvent was removed under vacuum, and the mixture was purified by chromatography (silica gel, 15%
MeOH/CH2Cl2); yield: 63%.
13.6.1.1.3.2.2
Variation 2: From an Amidoxime and a Carboxylic Acid Ester
Introductory Text
1,2,4-Oxadiazoles can be obtained by the treatment of esters and amidoximes with sodium metal in ethanol, [ 27 ,28 ] or with
sodium hydride in tetrahydrofuran ( Scheme 16 ).[ 28 ] Esters formed as intermediates during carboxylic acid activation are
not covered here, but are dealt with in Section 13.6.1.1.3.2.1. This methodology has been adapted to allow the solid-phase
synthesis of 1,2,4-oxadiazoles on a TentaGel support, using basic conditions at room temperature: this is discussed more
fully in Section 13.6.5.1.
Scheme 16 1,2,4-Oxadiazoles from an Ester and an

Amidoxime
[ 27 , 28 ]
3-(3-Alkyl-1,2,4-oxadiazol-5-yl)-1-methyl-1,2,5,6-tetrahydropyridines ( 30 ); General Procedure:[ 27 ]
The amidoxime 25 (8mmol) was added to a soln of Na (0.180g, 7.8mmol) in dry EtOH (20mL) containing 4-molecular
sieves (5g). The mixture was stirred at rt for 10min, and methyl 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate
hydrobromide (arecoline hydrobromide; 1.0g, 4.23mmol) was added. The mixture was heated at 80C for 12h, filtered, and
evaporated in vacuo. H2O (10mL) was added to the residue, and the mixture was extracted with Et 2O (325mL). The
combined extracts were dried (MgSO4) and evaporated in vacuo to give the product as the free base. The residual free base
was dissolved in EtOH (10mL) and a soln of oxalic acid in EtOH (10mL) was added. Addition of Et 2O and crystallization
gave the oxalate salt of the desired product, which could be recrystallized (EtOH/Et 2O).
13.6.1.1.3.2.3
Variation 3: From an Amidoxime and an Anhydride
Introductory Text
The use of carboxylic acid anhydrides to provide the single carbon for reaction with the amidoxime NCNO unit is
very well established,[ 1 6 , 26 , 27 , 81 , 99 104 ] and the method is noteworthy for allowing access to the parent unsubstituted 1,2,4oxadiazole.[ 13 , 99 ] The reaction proceeds via an intermediate O-acyl amidoxime 29 , which cyclizes upon heating in a suitable
solvent ( Table 3 ). The mechanism of the cyclization step has been studied, [ 105 ] but the intermediate is not normally isolated.
A wide range of 1,2,4-oxadiazoles can be prepared using this chemistry, including dipeptidomimetic oxadiazoles. [ 26 ] A
selection of 1,2,4-oxadiazoles that are available by this route is shown in Table 3 . A solid-phase synthesis of 1,2,4oxadiazoles by the reaction of an anhydride with a polymer-supported amidoxime has been developed (see Section 13.6.5.2).
Table 3 1,2,4-Oxadiazoles From an Amidoxime and an Acid Anhydride[ 1 6 , 13 , 26 , 27 ,

80 , 81 , 99 104 ]
Ethyl 5-Substituted 1,2,4-Oxadiazole-3-carboxylate Dipeptidomimetics from an Amidoxime and an Acid
Anhydride; General Procedure:[ 26 ]
DCC (1.5 equiv) was added to a Boc-protected L-amino acid (3 equiv) in dry CH 2Cl2, and the mixture was stirred at 0C for
1h. The mixture was filtered to remove N,N-dicyclohexylurea, and the filtrate was concentrated. The residual symmetrical
anhydride was dissolved in pyridine, a soln of ethyl 2-amino-2-(hydroxyimino)acetate ( 25 , R1=CO2Et; 1 equiv) in pyridine
was added dropwise, and the mixture was refluxed. Upon completion of the reaction (TLC), H 2O was added and the solvent
was evaporated. The residue was partitioned between H 2O and CH2Cl2, and the organic layer was washed with sat. aq
NaHCO3, aq HCl (pH2), brine, and H2O. The organic layer was dried (MgSO4), filtered, and concentrated, and the residue
was purified by column chromatography.
13.6.1.1.3.2.4
Variation 4: From an Amidoxime and an Acid Chloride
Introductory Text
The reaction of amidoximes 25 with acid chlorides gives O-acyl amidoximes 29 which, on heating, undergo ring closure to
form 1,2,4-oxadiazoles ( Table 4 ).[ 4 , 30 , 64 , 94 , 104 108 ] If the O-acylation is carried out at above 100C, the 1,2,4-oxadiazole is
formed directly. Recent modifications rely on the in situ formation of the O-acyl amidoxime in pyridine, followed by ring
closure on heating in pyridine.[ 30 , 94 ] Functionalities such as chloromethyl,[ 108 ] trichloromethyl,[ 30 ] (acetoxy)(alkyl)methyl,
[ 30 ]
and carboxylate[ 107 ] on the acid chloride allow further manipulations of the 3-substituent on 1,2,4-oxadiazole, whereas
the use of formyl fluoride allows access to monosubstituted 1,2,4-oxadiazoles [ 34 ] ( 9 , R2=H). Some examples are shown
in Table 4 .
Table 4 1,2,4-Oxadiazoles from Amidoximes and Acid Chlorides[ 30 , 64 , 94 , 101 , 104

108 ]
5-Methyl-3-phenyl-1,2,4-oxadiazole ( 9 , R1=Ph; R2=Me); Typical Procedure:[ 94 ]
AcCl (2.5mL) was added to a stirred suspension of benzamidoxime ( 25 , R1=Ph; 2.4g, 17.6mmol) in pyridine (4mL).
Upon reaction, the soln boiled, and heating was continued for 30min, after which the benzamidoxime could not be detected
by TLC. The soln was cooled to rt, diluted with H 2O (30mL), and cooled in a refrigerator overnight. The resulting precipitate
was collected by filtration, washed with H2O, and dried; yield: 2.26g (80%); mp 3941C.
13.6.1.1.3.3
Method 3: From an Amidoxime and a Nitrile Derivative
Introductory Text
This is a popular and versatile method that allows the nitrile carbon to function as the single-carbon unit which undergoes
reaction with the amidoxime 25 . A wide variety of nitrile-containing functionalities are suitable (Scheme 17 ), and the
reaction proceeds via the 2,3-dihydrooxadiazol-3-amine 31 , so that the nitrile carbon forms the C5 position of the 1,2,4oxadiazole.[ 6 , 80 , 109 114 ] As shown in Scheme 17 , a range of alkyl, aryl, and hetaryl nitriles react, [ 109 , 110 ] and the reaction is
particularly effective in the presence of zinc chloride and hydrochloric acid. [ 110 ]
Scheme 17 1,2,4-Oxadiazoles from Nitriles and

Amidoximes
[ 109 , 110 ]
The use of cyanates 32 (X=OAr1) allows access to 1,2,4-oxadiazol-5-amines 34 through the loss of HX from the 4,5dihydro-1,2,4-oxadiazol-4-amine 33 ( Scheme 18 ).[ 111 ] Similarly, the use of cyanogen halides 32 (X=Br or Cl) allows
access to 1,2,4-oxadiazol-5-amines 34 ,[ 80 , 112 ] and the use of cyanamides[ 113 ] 32 (X=NR4 2) and cyanoguanidine[ 114 ] 32 [X=
NHC(=NH)NH2] allows access to other 5-amino functionalities. Certain synthetic methods give rise to different positional
isomers, and 3-amino-substituted systems can also be formed: caution must therefore be exercised in the assignment of
structures to 1,2,4-oxadiazolamines synthesized in this fashion. [ 80 ]
Scheme 18 1,2,4-Oxadiazoles from the Reaction of

Amidoximes with Cyanates, Cyanogen Halides, and Cyanamide Derivatives
[ 80 , 111 114 ]
13.6.1.1.3.3.1
Variation 1: From an Amidoxime and an Alkyl or Aryl Nitrile
Introductory Text
Scheme 17 , above, shows the range of nitriles that can be used in this method. The reaction proceeds through the loss of
ammonia from an intermediate dihydro-1,2,4-oxadiazole 31 .
5-(2-Chloroethyl)-3-(3-nitrophenyl)-1,2,4-oxadiazole ( 9 , R1=3-O2NC6H4; R2=CH2CH2Cl); Typical
Procedure:[ 110 ]
3-Nitrobenzamidoxime (0.5g, 2.8mmol), ZnCl2 (1.11g, 8.14mmol), and 3-chloropropanenitrile (8g, 89mmol) were
dissolved in BuOAc, and HCl (0.20g, 5.5mmol) was introduced. The mixture was refluxed for 40min, cooled, diluted with
H2O (8mL), extracted with Et2O, and dried (MgSO4). The solvent was removed, and the residue was recrystallized (EtOH);
yield: 0.3g (42%); mp 90C.
13.6.1.1.3.3.2
Variation 2: From an Amidoxime and a Cyanate
Introductory Text
The use of cyanates, which were first reported in 1964, allows access to the 1,2,4-oxadiazolamines 34 ( Scheme18 ).[ 111 ] The
synthesis of the requisite cyanates usually begins with a cyanogen halide, and hence the synthesis of 1,2,4-oxadiazoles
directly from a cyanogen halide is probably a more accessible method (see Section13.6.1.1.3.3.3). A typical procedure
beginning from a cyanate is given below.
3-(4-Nitrophenyl)-1,2,4-oxadiazol-5-amine ( 34 , R1=4-O2NC6H4); Typical Procedure:[ 111 ]
The amidoxime 25 (R1=4-O2NC6H4; 3.6g, 20mmol) and phenyl cyanate (2.4g, 20mmol) were mixed in EtOH (20mL) at
rt. To the resulting O-(phenoxycarbimidoyl)amidoxime (2g, 7mmol) was added a soln of NaOEt in EtOH (50mL), and the
mixture was stirred at rt overnight. The resulting soln was neutralized with aq HCl, and the solvent was evaporated to give
the crude product, which was recrystallized (EtOH); yield: 0.9g (62% from the amidoxime); mp 299301C.
13.6.1.1.3.3.3
Variation 3: From an Amidoxime and a Cyanogen Halide
Introductory Text
The commercial availability of cyanogen halides 32 (X=halo) and the ready availability of amidoximes makes this a very
accessible method for preparing 1,2,4-oxadiazol-5-amines 34 .[ 80 , 112 ]
3-(2,6-Dichlorobenzyl)-1,2,4-oxadiazol-5-amine ( 34 , R1=2,6-Cl2C6H3); Typical Procedure:[80 ]
CAUTION: Cyanide salts can be absorbed through the skin and are extremely toxic.
BrCN (0.58g, 5.5mmol) was added to a stirred soln of (2,6-dichlorophenyl)acetamidoxime ( 25 , R1=2,6-Cl2C6H3; 1.1g, 5.3
mmol) and K2CO3 (0.55g, 5.5mmol) in MeOH (50mL). The mixture was stirred for 1.25h at rt, and then H 2O was added.
The white solid that precipitated was collected by filtration, washed well with H 2O, and dried in vacuo. The crude solid
(0.85g) was recrystallized (aq EtOH); yield: 0.32g (25%); mp 232234.5C.
13.6.1.1.3.4
Method 4: From an Amidoxime and an Orthoformate
Introductory Text
This method allows access to 3-substituted, 5-unsubstituted 1,2,4-oxadiazoles ( 9 , R2=H) ( Scheme 19 ).[ 115] Triethyl
orthoformate ( 35 , R2=H) is the most commonly used orthoformate,[ 30 , 33 , 34 , 115 118 ] but trimethyl orthoformate has also
been used.[ 118 ] The use of ethyl orthoacetate ( 35 , R2=Me) gives access to disubstituted systems, although a competitive
Beckmann-type rearrangement can lead to triazine N-oxides as the major product.[ 116 ] The 3-substituted, 5-unsubstituted
1,2,4-oxadiazoles are usually unstable (although some are unexpectedly stable), [ 34 ] and excess heating can lead to
decomposition.[ 1 6 , 116 ]
Scheme 19 1,2,4-Oxadiazoles from an Amidoxime and an

Orthoformate
[ 30, 33 , 34 , 115 118 ]
3-Substituted 1,2,4-Oxadiazoles 9 ; General Procedure:[ 33 ]
A mixture of the appropriate amidoxime (0.1mol) and HC(OEt)3 (100mL) was refluxed for 2h. The mixture was distilled
under reduced pressure and, in cases where the product was solid at rt, it was recrystallized [EtOAc/petroleum ether (bp 60
70C) or MeOH]. Excessive heating resulted in decomposition to give the nitrile (R 1CN), which was often isolated as a side
product.
13.6.1.1.3.5
Method 5: From an Amidoxime and a Cumulene or Heterocumulene
Introductory Text
The use of ketenes and isocyanates as the source of the carbon at C5 of the 1,2,4-oxadiazole ring has been known since the
early 1960s.[ 89 , 119 ] The ketene methodology is limited in scope,[ 119 ] but the isocyanate route offers more possibilities, and is
also a simpler method in practice. [ 89 ] With isocyanates, O-acylation of the amidoxime gives the O-acyl
product 36 ( Scheme 20 ), which undergoes cyclization in acetic anhydride to give the 1,2,4-oxadiazol-5-ol system 28 ,
representing a little-used but potentially useful route to this class of compounds.
Scheme 20 1,2,4-Oxadiazoles from an Amidoxime and an

Isocyanate
[ 89 ]
3-Aryl-1,2,4-oxadiazol-5-ols ( 28 , R1=aryl); General Procedure:[ 89 ]
The amidoxime 25 (R1=aryl) and an isocyanate were mixed at rt without a solvent, and then heated at 100C for 30min.
After cooling to rt, the O-acylamidoximes 36 were isolated; yield 75100%.
The O-acylamidoximes were dissolved in Ac2O, and the mixture was refluxed for 3h. The soln was evaporated to near
dryness, and the solid was collected by filtration to give the crude products. The crude products were recrystallized from a
suitable solvent (EtOH, MeOH, or their aqueous mixtures).
13.6.1.1.3.6
Method 6: From an Amidoxime and an Iminium Compound
Introductory Text
Vilsmeier salts 37 can provide the C5 carbon of 1,2,4-oxadiazoles, thereby allowing access to 5-unsubstituted 1,2,4oxadiazoles 38 ( Scheme 21 ).[ 33 , 120 ]
Scheme 21 1,2,4-Oxadiazoles from an Amidoxime and a

Vilsmeier Salt
[ 33 ,120 ]
Adaptations of the method are useful in allowing access to specific compounds. Thus, the use of chloroiminium
salts 39 ( Scheme 22 ) allows access to 1,2,4-oxadiazol-5-amines 40 or, under different conditions, 5-(methylsulfanyl)-1,2,4oxadiazole ( 41 ).[ 121 ]
Scheme 22 1,2,4-Oxadiazoles from Chloroiminium

Salts
[ 121 ]
In an interesting intramolecular version of the iminium approach, the 3-(methylsulfanyl)-2-azaprop-3-eniminium

salts 42 undergo cyclization and ring opening to furnish the 5-(-aminoalkyl)-1,2,4-oxadiazoles 43 upon treatment with
methanolic hydroxylamine ( Scheme 23 ; see also Section 13.6.1.3.1.3).[ 122 ]
Scheme 23 Intramolecular Ring Closure onto an Iminium

Carbon
[ 122 ]
3-(4-Chlorophenyl)-1,2,4-oxadiazole ( 38 , R1=4-ClC6H4); Typical Procedure:[ 33 ]
A soln of 4-chlorobenzamidoxime (8.5g, 50mmol) in Et2O was added with stirring to DMFPOCl3 complex[ 123 ](0.1mol).
The temperature was maintained at 10C for 10min, and then the solvent was then removed at 60C. The residue was
washed with H2O (2150mL), and the crude product was recrystallized (MeOH); yield: 7.2g (80%); mp 100102C.
13.6.1.1.3.7
Method 7: From an Amidoxime and an Imino Ether, Lactim Ether, Imidic Chloride, or
Alkoxyimidoyl Compound
Intoductory Text
Imino ethers 44 ( Scheme 24 ),[ 64 , 124 126 ] alkoxyimidoyls,[ 124 ] lactim ethers 45 (X=OR2),[ 127 ] and imidic chlorides 45 (X=
Cl)[ 127 ] ( Scheme 25 ) are imine functionalities that can provide the single C5 carbon of the 1,2,4-oxadiazole nucleus upon
reaction with an amidoxime. The imino ether methodology provides an easy route to 3,5-disubstituted 1,2,4-oxadiazoles. The
lactim ether and imidic chloride route is useful in providing access to the 5-(alkylamino) systems 46 ( Scheme 25 ).[ 127 ]
Scheme 24 1,2,4-Oxadiazoles from Imino Ethers and

Amidoximes
[ 64 , 124 126 ]
Scheme 25 1,2,4-Oxadiazoles from Imidic Chlorides or

Lactim Ethers
[ 127 ]
Benzamidoxime (13.6g, 100mol) and the imino ether 44 (R2=Me; R3=Et; 15g, 121mol) in EtOH (70mL) were refluxed
overnight. The precipitated NH4Cl was removed by filtration, and the solvent was removed by distillation, to leave the crude
product, which was purified by sublimation; yield: 14g (87%); mp 4142C.
13.6.1.2 By Formation of One ON Bond

13.6.1.2.1 Fragment OCNCN
13.6.1.2.1.1
Method 1: From Nitrene Precursors
Introductory Text
The in situ generation of nitrenes, of general structure 47 , allows cyclization to give the 1,2,4-oxadiazoles 9 (Table 5 ).
[ 128 132 ]
The nitrenes can be generated from a variety of precursors, and two of the most useful methods are given as
variations, below.
Table 5 1,2,4-Oxadiazoles from Nitrenes[ 128 132 ]

13.6.1.2.1.1.1
Variation 1: By Using Nitrenes Derived from N-Acylamidrazones
Introductory Text
On thermolysis, N-acylamidrazones 49 (R1=NMe3)[ 128 ] and the related acylated sulfinylimines 49 (R1=SMe2)[129 ] give
excellent yields of 1,2,4-oxadiazoles via the corresponding nitrenes 47 ( Scheme 26 ). The N-acylamidrazones 49 (R1=
NMe3) can be obtained from the readily available imino-1,1,1-trimethylhydrazinium salts 48 (R1=NMe3) upon treatment
with an acid chloride or acid anhydride. [ 128 ] These methods allow access to 3-(alkyl/aryl)-5-(aryl/alkyl)-substituted systems.
Scheme 26 Synthesis via Nitrenes Derived from NAcylamidrazones

[ 128 ,129 ]
A mixture of inner salt 48 (X=NMe3; R1=Ph; 2.0g, 11mmol),[ 128 ] Ac2O (1.3mL), anhyd Na2CO3 (0.74g, 7mmol), and
CH2Cl2 (15mL) was stirred vigorously for 1h. H2O (10mL) was added to dissolve the inorganic material. The aqueous layer
was saturated with Na2CO3 and extracted with CH2Cl2. The combined extracts were dried (MgSO4) and evaporated to give the
crude N-acylamidrazone 49 (X=NMe3; R1=Ph; R2=Me); yield: 1.0g (41%); mp 169170C. This was purified by
recrystallization (EtOH); yield: 48%; mp 186188C.
The N-acylamidrazone (1.0g, 5.6mmol) was heated at 190C for 5min to give the title compound; yield: 0.56g (77%); mp
2729C.
13.6.1.2.1.1.2
Variation 2: By Using Nitrenes Derived Ultimately from Trimethylsilyl Azide
Introductory Text
The reaction of trimethylsilyl azide with an aroyl isocyanate gives the corresponding nitrene 51 through loss of nitrogen
from the proposed intermediate 50 ( Scheme 27 ).[ 130 ] Cyclization of the nitrene gives an 1,2,4-oxadiazol-3-ol ( 9 , R1=OH).
This approach represents an efficient entry to such systems. The corresponding 3-siloxy-substituted systems can occasionally
be isolated, but are easily and quantitatively converted into 1,2,4-oxadiazol-3-ols.
Scheme 27 Synthesis via Nitrenes Derived from

Trimethylsilyl Azide
[ 130 ]
5-(4-Chlorophenyl)-1,2,4-oxadiazol-3-ol ( 9 , R1=OH; R2=4-ClC6H5); Typical Procedure:[ 130 ]
A mixture of TMSN3 (3.4g, 29.5mmol) and 4-chlorobenzoyl isocyanate (2.7g, 14.9mmol) was refluxed for 6h, and then
the mixture was evaporated in vacuo to leave 5-(4-chlorophenyl)-3-(trimethylsiloxy)-1,2,4-oxadiazole (9 , R1=OTMS; R2=
4-ClC6H4) as a yellow crystalline solid; yield: 3.33g (83%); mp 7678C.
A soln of this material (3.30g, 12.39mmol) in EtOH (10mL) was stirred at rt for 30min and then evaporated in vacuo.
Recrystallization of the residue [hexane/benzene (CAUTION: carcinogen)] gave the title compound as colorless needles;
yield: 2.42g (quant; 83% from the isocyanate); mp 223224C.
13.6.1.3 By Formation of One OC Bond

13.6.1.3.1 Fragment ONCNC
13.6.1.3.1.1
Method 1: From N-Acylamidoximes
Introductory Text
N-Acylamidoximes 52 cannot usually be isolated, and cyclize spontaneously at rt to give 1,2,4-oxadiazoles (Scheme 28 ). NAcylamidoximes, therefore, are often formed as intermediates in several of the reported routes to 1,2,4-oxadiazoles, [ 1 6 ] and
are mostly dealt with in Sections 13.6.1.1.2.1 and 13.6.2. It is important to note that N-acylamidoximes cannot be prepared
by the N-acylation of amidoximes as O-acylation is much faster. [4 , 6 ] The O-acylation of amidoximes and the subsequent
cyclization of the O-acylamidoximes obtained are dealt with elsewhere (see Sections 13.6.1.1.3, 13.6.1.4.2.1,
and 13.6.1.4.2.2).
Scheme 28 Cyclization of N-Acylamidoximes

13.6.1.3.1.2
[ 1 6 ]
Method 2: From N-(Dicyanovinyl)amidoximes
Introductory Text
The readily available N-(dicyanovinyl)amidoximes 54 (from 53 ; Scheme 29 ) undergo cyclization with the elimination of
malonitrile to furnish 1,2,4-oxadiazoles 9 ,[ 133 , 134 ] a route that is noteworthy in that it allows the synthesis of 5-unsubstituted
1,2,4-oxadiazoles ( 9 , R2=H).
Scheme 29 1,2,4-Oxadiazoles from N(Dicyanovinyl)amidoximes
[ 133 , 134 ]
3,5-Diphenyl-1,2,4-oxadiazole ( 9 , R1=R2=Ph):[ 134 ]
NH2OHHCl (0.209g, 3mmol) and methyl N-(2,2-dicyano-1-phenylvinyl)benzenecarbimidothioate ( 53 , R1=Ph; R2=Ph;
0.303g, 1mmol) were added to a soln of NaOMe (0.178g, 3.3mmol) in dry MeOH (25mL). The mixture was stirred at rt
for 48h and then poured into H2O to give a precipitate that was collected by filtration and recrystallized (MeOH); yield:
0.200g (90%); mp 106107C.
13.6.1.3.1.3
Method 3: Cyclization of the Oxime Oxygen onto an Iminium Carbon
Introductory Text
The intramolecular cyclization of the oxime oxygen onto an iminium carbon derived from 3-(methylsulfanyl)-2-azaprop-3eniminium salts 42 is accompanied by ring opening to give the corresponding 5-(-aminoalkyl)-1,2,4oxadiazoles 43 ( Scheme 23 )[ 122 ] (see Section 13.6.1.1.3.6).
5-(-Aminoalkyl)-1,2,4-oxadiazoles ( 43 ); General Procedure:[ 122 ]
NH2OHHCl (35g, 503mmol) was dissolved in boiling MeOH (200mL), and a soln of Na (12.5g, 500mmol) in MeOH
(250mL) was added. The soln was filtered hot, then diluted to a final volume of 500mL with MeOH. The 3(methylsulfanyl)-2-azaprop-3-enium iodide 42 (10mmol) was added to a portion of the freshly prepared soln of
hydroxylamine (15mL), and the mixture was refluxed for 30min. The product precipitated out as the hydroiodide salt, and
was collected by filtration and recrystallized (EtOH).
For example, 5-[(methylamino)methyl]-1,2,4-oxadiazol-3-amine ( 43 , R1=NH2; R2=Me; n=1) was obtained by this
method; yield: 53%; mp 183185C
13.6.1.4 By Formation of One NC Bond

13.6.1.4.1 Fragment NCONC
13.6.1.4.1.1
Method 1: From Imidates
Introductory Text
There is evidence in the literature that the O-substituted imidates 55 (X=NH2) undergo cyclization through attack on the
imidate nitrogen ( Scheme 30 ).[ 105 , 110 ] 15N-Labeled systems 55 (X=15NH2) showed loss of labeled ammonia, with no
incorporation of the label into the 1,2,4-oxadiazole, [ 110 ] showing that ring closure occurs through the fragment NCON
C and not through the alternative fragment NCNOC. The cyclization precursors 55 are synthesized by the
reaction of an amidoxime with a nitrile.
Scheme 30 Conversion of Imidate Derivatives into 1,2,4-Oxadiazoles
[ 105 ,110 ]
3,5-Bis(chloromethyl)-1,2,4-oxadiazole ( 9 , R1=R2=CH2Cl); Typical Procedure:[ 110 ]
HCl(g) (0.34g, 9.3mmol) was passed through a soln of 1-15N-labelled 2-chloro-N-hydroxyethanimidamide (1g, 9.1mmol),
ZnCl2 (5g, 37mmol), and ClCH2CN (5g, 66.2mmol) in BuOAc (8mL). The mixture was refluxed for 20min to effect
cyclization of the intermediate 55 (X=15NH2; R1=R2=CH2Cl). After cooling, the mixture was diluted with H 2O, extracted
with Et2O, and dried (MgSO4). The solvent was removed, and the residue was distilled; yield: 0.98g (64%); bp 68C/1
Torr; m/z=166 (168) (170), (M+). 15N content=0%.
13.6.1.4.2 Fragment NCNOC

13.6.1.4.2.1
Method 1: From O-Acylamidoximes Derived from Amidoximes
Introductory Text
The cyclization of an O-acylamidoxime 29 results in the formation of 1,2,4-oxadiazoles ( Scheme 31 ). Most modern
approaches to 1,2,4-oxadiazoles incorporate the in situ generation of the O-acylamidoxime, which then cyclizes
spontaneously without isolation.[ 6 , 25 , 94 ] Many such approaches involve the reaction of a single-carbon unit with the
amidoxime fragment NCNO (See Section 13.6.1.1.3, particularly Sections 13.6.1.1.3.1 and13.6.1.1.3.2). However,
some procedures do detail the isolation of intermediate O-acylamidoximes, and a typical procedure for the cyclization of
the N-aryl-2-oxo-ethyl O-acylamidoximes 29 (R1=CH2CONHAr1) into the usefully substituted 2-(1,2,4-oxadiazol-5-yl)-Narylacetamides 9 (R1=CH2CONHAr1) is given below.[ 135 ]
Scheme 31 Cyclization of O-Acylamidoximes
[ 6 , 25 , 94 , 135 ]

2-{5-[(4-Nitrophenoxy)methyl]-1,2,4-oxadiazol-3-yl}-N-(2,4,6-trichlorophenyl)acetamide [9 , R1=(2,4,6Cl3C6H2)NHCOCH2; R2=4-O2NC6H4OCH2]; Typical Procedure:[ 135 ]
A soln of the propioamidoxime 29 [R1=(2,4,6-Cl3C6H2)NHCOCH2; R2=4-O2NC6H4OCH2; 13.6g, 28.7mmol][ 135] in xylene
(210mL) was refluxed using a DeanStark separator for 2h. The solvent was removed under reduced pressure, and the
residual oil was recrystallized (hexane); yield: 8.6g (65%); mp 180181C.
13.6.1.4.2.2
Method 2: Cyclization of O-Acylamidoximes Formed as Intermediates from Purine Precursors
Introductory Text
The treatment of 9H-purin-6-amine 1-oxide ( 56 , R1=R2=H) ( Scheme 32 ) with acetic anhydride yields the 3-[(4amino)imidazolyl]-substituted 1,2,4-oxadiazole 58 (R3=NH2; R4=H).[ 136 ] 9H-Purine-2,6-diamine 1-oxide ( 56 , R1=NH2;
R2=H) and 6-amino-9H-purin-8-ol 1-oxide ( 56 , R1=H; R2=OH) behave in a similar fashion, giving the corresponding
1,2,4-oxadiazoles 58 (R3=NHAc; R4=H) and 58 (R3=NHAc; R4=OAc), respectively.[ 136 ] The reactions proceed via the
intermediate O-acylamidoximes 57 .
Scheme 32 Synthesis of 1,2,4-Oxadiazoles from

Purines
[ 136 ]
4-(5-Methyl-1,2,4-oxadiazol-3-yl)-1H-imidazol-5-amine ( 58 , R3=NH2; R4=H); Typical Procedure:[ 136 ]
9H-Purin-6-amine 1-oxide ( 56 , R1=R2=H; 1.0g, 6.6mmol) was dissolved in Ac2O (15mL). The soln was brought to
reflux, cooled, and poured into H2O (40mL). The resulting soln was evaporated to dryness in vacuo, and 1M HCl (50mL)
was added to the residue. The resulting mixture was refluxed for 3h, and then evaporated to dryness, and the product was
recrystallized (AcOH); yield: 1.0g (75% as HCl salt); mp 204210C (dec).
13.6.1.4.2.3
Method 3: Staudinger/Aza-Wittig Reaction of O-Acylazidooximes
Introductory Text
The aza-Wittig reaction has been used to construct a wide range of heterocycles containing a C=N bond, and its use in
construction of the 1,2,4-oxadiazole ring was reported by Molina and co-workers in 1986. [ 137 ] The azidoximes 59 required
for such a procedure are available from the reaction of chlorooximes (hydroxamic acid chlorides) with sodium azide
( Scheme 33 ). Reaction of azidoximes 59 with acid chlorides in basic media at ice temperature gives the Oacylazidoximes 60 in 3599% yield. The Staudinger reaction of compounds 60 with triphenylphosphine gives the
corresponding iminophosphoranes 61 , which, on heating in boiling toluene, undergo the expected aza-Wittig reaction to
give the 1,2,4-oxadiazoles 9 .[ 137 ]
Scheme 33 A Staudinger/Aza-Wittig Route to 1,2,4Oxadiazoles

[ 137 ]
3,5-Diphenyl-1,2,4-oxadiazole ( 9 , R1=R2=Ph); Typical Procedure:[ 137 ]
Ph3P (2.62g, 10mmol) in dry CH2Cl2 (10mL) was added dropwise over 15min to an ice-cold soln of the O-acylazidoxime
derivative 60 (R1=R2=Ph; 2.66g, 10mmol) in dry CH2Cl2 (20mL). The mixture was stirred at 05C for 20h, and then the
solvent was evaporated under reduced pressure. The residue was recrystallized [hexane/benzene (CAUTION: carcinogen)]
to give the iminophosphorane 61 (R1=R2=Ph); yield: 3.95g (79%); mp 108110C.
A soln of the iminophosphorane 61 (10g, 20mmol) in dry toluene (20mL) was refluxed for 15h. The solvent was
evaporated under reduced pressure, and the residue was treated with EtOH to dissolve the Ph 3PO side product. The
remaining solid was collected by filtration and crystallized (EtOH) to give the title compound; yield: 4.5g (99%); mp 115
116C.
13.6.2 Synthesis by Ring Transformation

Introductory Text
Several other heterocycles can be transformed into the 1,2,4-oxadiazole nucleus. [ 5 , 6 ] Many of these routes proceed via Nacylamidoxime intermediates, which are usually not isolated or characterized. Section 13.6.1.1.2.1deals with the synthesis of
1,2,4-oxadiazoles from N-acylamidoximes in general terms, but does not involve N-acylamidoximes derived from
heterocycles. Heterocycles that can be transformed into 1,2,4-oxadiazoles include benzoxazinium salts, [ 138 ] quinazolinone
derivatives,[ 139 ] thiadiazolium salts,[ 140 ] a range of imidazoles, [ 61 ,141 145 ] 1,3-oxazoles,[ 87 , 88 ] 1,2,5-oxadiazoles,[ 146 ] tetrazoles,
[ 147 ]
and a variety of others.[ 6 , 7 , 134 ]Many of these methods, however, lack general applicability, and only those with the
potential for either the synthesis of a range of 1,2,4-oxadiazoles, or which can be used for the synthesis of rare but important
1,2,4-oxadiazoles are included here.
13.6.2.1 Method 1: From Tetrazoles

Introductory Text
The reaction of tetrazoles 62 with nitrile oxides gives, as one of the products, the N-substituted tetrazole 63 , which, upon
thermolysis, yields the 1,2,4-oxadiazoles 9 ( Scheme 34 ).[ 147 ] With tetrazole ( 62 , R2=H), this route allows access to
mixtures of 5-amino- and 5-unsubstituted 1,2,4-oxadiazoles. With tetrazoles ( 62 , R2H), fair-to-excellent yields of
disubstituted 1,2,4-oxadiazoles are obtained.
Scheme 34 1,2,4-Oxadiazoles from Tetrazoles
[ 147 ]

1,2,4-Oxadiazoles from Tetrazoles; General Procedure:[ 147 ]
Et3N (20% molar excess) was added dropwise to a stirred soln of the tetrazole (20mmol) and the hydroximoyl chloride (20
mmol) in dioxane (50mL) at rt. Stirring was continued until the nitrile oxide spot was no longer detectable by TLC. The
precipitated Et3NHCl was removed by filtration, and the filtrate was evaporated to dryness and purified, usually by
recrystallization [cyclohexane/benzene (CAUTION: carcinogen)] or by column chromatography (silica gel, EtOAc/hexane).
The purified hydroximoyltetrazole was suspended in an appropriate hydrocarbon (usually xylene), and refluxed until TLC
indicated complete conversion of the substrate. The residue was recrystallized from an appropriate solvent or purified by
column chromatography (silica gel, EtOAc/hexane). As an example, 3-(4-nitrophenyl)-1,2,4-oxadiazole was obtained; yield:
65%; mp 162164C.
13.6.2.2 Method 2: From 1,2,4-Oxadiazoles

Introductory Text
Mononuclear heterocyclic rearrangements involving oxadiazoles with XYZ side chains, often known as BoultonKatritzky
rearrangements,[ 148 ] can, when XYZ is NCO, lead to the formation of one 1,2,4-oxadiazole from another ( Scheme 35 ).
Such rearrangements are known as isoheterocyclic rearrangements, [ 149 151 ] and a typical example is the conversion of the 3(acetylamino)-5-aryl-1,2,4-oxadiazoles 64 into the 3-(aroylamino)-5-methyl-1,2,4-oxadiazoles 65 .[ 152 154 ]
Scheme 35 1,2,4-Oxadiazoles from Other 1,2,4Oxadiazoles
[ 152 154 ]
4-Methoxy-N-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide ( 65 , Ar1=4-MeOC6H4); Typical Procedure:[ 152 ]
N-[(5-(4-Methoxyphenyl)-1,2,4-oxadiazol-3-yl]acetamide ( 64 , Ar1=4-MeOC6H4; 0.2g, 0.86mmol) in freshly prepared
anhyd MeOH (100mL), in a quartz tube, was degassed for 20min by N 2-bubbling, and then irradiated at 254nm in an
immersion-well apparatus, equipped with a running H2O system, using a Hg lamp (Helios Italquartz, 17W). Irradiation was
continued for 10h, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography
(silica gel, petroleum ether/EtOAc); yield: 0.14g (70%). The purity of the product and the progress of the reaction were
monitored by HPLC (Perkin-Elmer Series 10) instrument, using a C-18 SIL-X-10 Perkin-Elmer column (25cm4.6mm
diameter) eluting with H2O/MeCN (7:3 v/v) at a flow rate of 2.0mLmin1, while monitoring the optical density at 254nm.
13.6.2.3 Method 3: From 1,2,5-Oxadiazoles

Introductory Text
Photolysis of the 3-(aroylamino)-1,2,5-oxadiazoles 66 results in the loss of a nitrile fragment to give the proposed
intermediates 67 ( Scheme 36 ). Reaction with a primary or secondary amine then gives the N-acylamidoximes68 that
cyclize to give 1,2,4-oxadiazol-3-amines 69 .[ 145 , 146 ] Dibenzoylfuroxan can also be converted into (3-hydroxy-1,2,4oxadiazol-5-yl)(phenyl)methanone by mild hydrolysis, [ 145 ] but the process lacks further applicability.
Scheme 36 1,2,4-Oxadiazol-3-amines from 3(Aroylamino)-1,2,5-oxadiazoles
[ 146 ]
1,2,4-Oxadiazol-3-amines ( 69 ); General Procedure:[ 146 ]
A 3-(aroylamino)-1,2,5-oxadiazole 66 was irradiated at 254nm by using low-pressure Hg lamps (17W) in an immersion

apparatus equipped with H2O circulation at 05C. The irradiation was performed in the presence of an appropriate source of
nucleophilic nitrogen (aq NH3, ethanolic MeNH2 or Me2NH, or an excess of pyrrolidine, piperidine or BuNH2 in MeOH) to
give the corresponding 1,2,4-oxadiazol-3-amine 69 in 4550% yield, together with the appropriate nitrile.
13.6.2.4 Method 4: From Imidazoles

Introductory Text
Early work in this area showed that 2,4-disubstituted 5-nitrosoimidazoles 70 undergo hydrolytic ring opening and subsequent
ring closure to furnish the 3-acyl-1,2,4-oxadiazoles 71 ( Scheme 37 ).[ 141 , 142 ] 2,4-Disubstituted imidazoles 72 can be
oxidized to give 3,5-disubstituted 1,2,4-oxadiazoles 9 , via a formyliminoamide intermediate, [ 143 , 144 ] although difficulty in
accessing the imidazoles, and the availability of simpler alternative for the syntheses of 3,5-disubstituted 1,2,4-oxadiazoles
limits the usefulness of this reaction.
Also illustrated in Scheme 37 is a useful entry to the less-accessible 3-acyl- and 3-aroyl-1,2,4-oxadiazol-5-amines 75 , by
treatment of the imidazol-2-amines 73 with isopentyl nitrite, followed by hydrolysis of the intermediate 5(hydroxyimino)imidazol-2-amines 74 .[ 145 ] As this intermediate is tautomeric with a 5-nitrosoimidazole, the mechanism is
analogous to that shown for the hydrolysis of imidazole 70 . Interestingly, the -radiation sensitizer metronidazole 76 yields
the 1,2,4-oxadiazole 78 almost quantitatively upon irradiation, a reaction that is believed to proceed via the hydroxyimino
intermediate 77 .[ 61 ]
Scheme 37 1,2,4-Oxadiazoles from Imidazoles
[ 61 , 141 145 ]
3-Benzoyl-1,2,4-oxadiazol-5-amine ( 75 , R1=Ph); Typical Procedure:[ 145 ]
Isopentyl nitrite (5.9mL, 44mmol) was added dropwise to a soln of 4-phenyl-1H-imidazol-2-amine hydrochloride ( 73 , R1
=Ph; 8.4g, 43mmol) in H2O (175mL) and glacial AcOH (250mL) over 15min at 05C. The soln was stirred for 1h at 0
C and then for 3h at rt. The mixture was concentrated in vacuo at rt to give a solid that was collected by filtration and
washed with AcOH (10mL) and then with Et2O (10mL). Recrystallization (MeOH/Et2O) gave 4(5)-(hydroxyimino)-5phenyl-4H-imidazol-2-amine hydrochloride ( 74 , R1=Ph); yield: 8.6g (89%); mp 158160C.
A suspension of this material (5.4g, 21mmol) in H 2O (60mL) was heated to boiling. After a few mins, the solid dissolved
and a precipitate formed. The mixture was refluxed for 1h, then cooled. The product was collected, washed with H 2O, and
dried; yield: 3.8g (98%); mp 193C.
13.6.3 Aromatization
Introductory Text
This section deals only with those dihydro-1,2,4-oxadiazoles that can be isolated and are subsequently oxidized to the fully
aromatic 1,2,4-oxadiazole in a separate step. In situ oxidation of dihydro-1,2,4-oxadiazoles, where aromatization is
spontaneous, is dealt with in Section 13.6.1.1.1.2.
13.6.3.1 Method 1: By Dehydrogenation

Introductory Text
Forced loss of hydrogen from isolable 4,5-dihydro-1,2,4-oxadiazoles 79 can be carried out by using potassium
permanganate,[ 155 , 156 ] chlorine in carbon tetrachloride,[ 98 ] sodium hypochlorite,[ 157 ] N-chlorosuccinimide,[157 ] oxygen in air,
[ 158 ]
or a variety of other oxidants ( Table 6 ).[ 159 ] The ready availability of 4,5-dihydro-1,2,4-oxadiazoles 79 by the
condensation of an aldehyde with an amidoxime [ 159 , 160 ] has made this an attractive and popular entry to fully unsaturated
1,2,4-oxadiazoles.
Table 6 Oxidation of 4,5-Dihydro-1,2,4-oxadiazoles[ 98 , 155 159 ]

3-(2,3,5-Tri-O-benzoyl--D-ribofuranosyl)-5-methyl-1,2,4-oxadiazole ( 9 , R1=2,3,5-Tri-O-benzoyl--Dribofuranosyl; R2=Me); Typical Procedure:[ 98 ]
The dihydrooxadiazole 79 (R1=2,3,5-tri-O-benzoyl--D-ribofuranosyl; R2=Me; 0.02mol, 10mg) was treated with a soln of
Cl2 in CCl4 (1M; 1mL) in the dark for 10min. The product was isolated by preparative TLC; yield: quant.
13.6.3.2 Method 2: By the Elimination of HX or YX

Introductory Text
The elimination of a molecule of YX (XH) from the isolable dihydro-1,2,4-oxadiazoles 12 gives 1,2,4oxadiazoles9 ( Scheme 38 ).[ 4 , 6 , 66 , 67 ] Interestingly, this type of reaction can also occur in fused dihydro-1,2,4-oxadiazoles,
for example compounds 80 [ 65 ] and 82 .[ 70 ]
Scheme 38 Elimination
of YX from Dihydro-1,2,4-oxadiazoles
[ 65 , 66 , 70 ]

5-(2-Fluoro-1,1,2-trimethylpropyl)-3-substituted 1,2,4-Oxadiazoles 81 ; General Procedure:[65 ]
AgBF4 (1.25mmol, 2.5 equiv) was added to a stirred soln of the 4-oxa-1,3-diazabicyclo[3.2.0]hept-2-ene 80 [ 65] (0.5mmol,
1.0 equiv) and dry, freshly distilled 2,4,6-trimethylpyridine (2mmol, 4.0 equiv) in dry CH2Cl2 (10mL) at 0C, under dry
argon. The mixture was stirred at 0C for 23hours while monitoring by TLC. Upon completion of the reaction, the mixture
was filtered, and to the filtrate was added an equal volume of petroleum ether (6080C). The resulting precipitate of
collidine salts was removed by filtration, and the filtrate was concentrated by rotary evaporation at 10Torr to leave a yellow
oil. Purification by flash chromatography [silica gel, petroleum ether (6080C)/EtOAc] gave the 5-(2-fluoro-1,1,2trimethylpropyl)-substituted oxadiazole.
For example, 3-phenyl-5-(2-fluoro-1,1,2-trimethylpropyl)-1,2,4-oxadiazole ( 81 , R1=Ph) was obtained as a colorless oil
from bicycle 80 (R1=Ph; 0.140g, 0.6mmol); yield: 0.097g (81%).
13.6.4 Synthesis by Substituent Modification

13.6.4.1 Substitution of Existing Substituents
13.6.4.1.1 Of Hydrogen
13.6.4.1.1.1
Method 1: By Metals
Introductory Text
The 1,2,4-oxadiazole nucleus 38 shows very poor reactivity towards electrophilic attack at carbon, and the only example is
the replacement of hydrogen in 5-unsubstituted systems through electrophilic mercuration (e.g., 84 ,Scheme 39 ).[ 21 , 161 ]
Scheme 39 Mercuration of 5-Unsubstituted 1,2,4Oxadiazoles
[ 21 , 161 ]
Chloro(3-phenyl-1,2,4-oxadiazol-5-yl)mercury ( 84 , R1=Ph):[ 21 ]
CAUTION: Mercury(II) chloride is a poison by ingestion and is toxic by skin contact. When heated to decomposition, it
emits toxic fumes of mercury.
To a soln of HgCl2 (80g, 0.295mol) in distilled H2O (1L) was added NaOAc3H2O (27.2g, 0.20mol) and 3-phenyl-1,2,4oxadiazole (14.6g, 0.1mol) as a soln in EtOH (100mL). The mixture was stirred for 1 month, after which the EtOH was
removed from the soln by evaporation, and the title compound precipitated from soln; yield: 17.1g (45%); mp 170C.
13.6.4.1.2 Of Metals
13.6.4.1.2.1
Method 1: By Heteroatoms
Introductory Text
The displacement of the mercurio group from 5-mercurio-1,2,4-oxadiazoles, such as compound 84 , with iodine, occurs in
excellent yield, to give, for example, the 5-iodo compound 85 ( Scheme 39 ).[ 21 ] Chlorine will also displace the mercury
group to furnish the corresponding 5-chloro compound, although yields are low. [ 21 , 161 ]
5-Iodo-3-phenyl-1,2,4-oxadiazole ( 85 , R1=Ph); Typical Procedure:[ 21 ]
An aqueous soln containing I2 (51g, 200mmol) and KI (166g, 100mmol) was added over 2.5h to a stirred suspension of the
mercurio compound 84 (R1=Ph; 38.2g, 100mmol) in distilled H2O (500mL) at rt. After 2h, the excess I 2 was destroyed by
the addition of Na2S2O3. The soln was extracted with CCl 4 (3100mL), dried (CaCl2), and evaporated to give the title
compound, which was stored at 0C in the dark; yield: 21.8g (80%); mp 100101C.
13.6.4.1.3 Of Carbon Functionalities

13.6.4.1.3.1
Method 1: By Heteroatoms
Introductory Text
The trichloromethyl group in 5-(trichloromethyl)-substituted 1,2,4-oxadiazoles 86 is remarkably easily displaced by a range
of nucleophiles ( Scheme 40 ),[ 4 6 , 30 , 80 , 162 164 ] such as alkoxides,[ 30 ] primary and secondary amines,[ 80 , 162 , 163 ] or guanidine.
[ 164 ]
The method therefore represents a valuable entry to 1,2,4-oxadiazoles 87 (Nu=optionally substituted amino, alkoxy,
hydroxy). Note that 3-(trichloromethyl)-substituted 1,2,4-oxadiazoles, on the other hand, tend to undergo nucleophilic
displacement of the side-chain chlorine atoms (see Section 13.6.4.3.3).
Scheme 40 Substitution of the 5-(Trichloromethyl)

Group
[ 21 , 30 , 80 , 162 164 ]
5-Substituted 3-{3,5-Dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl}-1,2,4-oxadiazoles { 87 , R1=3,5dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl; Nu=NMe 2, NHMe, OEt, or OMe}; General
Procedure:[ 30 ]
Freshly prepared sodium alkoxide (1.5 equiv) or 40% aq amine (5mL) was added to dry DMF (35mL). The
(trichloromethyl)oxadiazole 86 {R1=3,5-dimethyl-4-[3-(3-methylisoxazol-5-yl)propoxy]phenyl} was added, and the
mixture was stirred at rt for 30min (R2=OMe, NMe2, or NHMe) or 18h (R2=OEt). The mixture was diluted with H 2O and
extracted with EtOAc (3). The combined extracts were washed with H 2O and brine, dried, and concentrated in vacuo to
give the crude product, which was purified by chromatography.
13.6.4.1.4 Of Heteroatoms
13.6.4.1.4.1
Method 1: By Carbon
Introductory Text
This is a seldom reported, but potentially useful transformation. The 1,2,4-oxadiazol-3-amine 88 is converted into the
corresponding nitrile 89 ( Scheme 41 ) by diazotization followed by reaction with tetrabutylammonium cyanide.
[ 165 ]
Attempts to achieve the introduction of the nitrile group by reacting the corresponding chloro compound with cyanide
were unsuccessful,[ 165 ] as were similar attempts with other 3-halo-substituted 1,2,4-oxadiazoles. [ 52 ]
Scheme 41 Synthesis of a 1,2,4-Oxadiazol-3-carbonitrile

through Diazotization
[ 165 ]
5-(1-Azabicyclo[2.2.2]oct-3-yl)-1,2,4-oxadiazole-3-carbonitrile Oxalate ( 89 ):[ 165 ]
The amine 88 (0.78g, 4.0mmol) in dry DMF (40mL) was cooled to 10C and treated with dry 0.85M HCl in DMF (14mL,
12mmol) and isoamyl nitrite (1.6mL, 12mmol) for 3.5h. Bu4NCN (3.2g, 12mmol) in DMF (10mL) was added, and the
mixture was allowed to warm slowly to rt. The residue obtained after removal of the solvent was partitioned between Et 2O
and aq K2CO3. The Et2O layer was dried and evaporated, and the residue was purified by chromatography (alumina). The
product was crystallized as the hygroscopic oxalate salt; yield: 35mg (3%).
13.6.4.1.4.2
Method 2: By Another Heteroatom
Introductory Text
The replacement of a heteroatom in either the 3- or the 5-position of the starting 1,2,4-oxadiazole nucleus 90with another
heteroatom is a widely employed and useful procedure in 1,2,4-oxadiazole chemistry. [ 4 6 , 52 , 59 ,145 , 164 168 ] The mode of
reactivity is usually nucleophilic displacement, [ 4 6 , 59 , 166 , 167 ] although oxadiazolamines require the preliminary step of
diazotization ( Table 7 ).[ 4 6 , 165 , 168 ]
Table 7 Substitution of One Heteroatom by Another Heteroatom[ 59 , 145 , 165 168 ]

1-[3-(4-Nitrophenyl)-1,2,4-oxadiazol-5-yl]piperidine ( 9 , R1=4-O2NC6H4; R2=1-Piperidyl):[59 ]
A soln of the oxadiazole 90 [X=4-O2NC6H4; Y=2-Cl-2,6-(O2N)2C6H2S; 0.600g, 1.4mmol][ 59 ] and piperidine (10mL) in
CHCl3 (30mL) was refluxed for 2d. The solvent and the excess piperidine were removed and the residue was purified by
chromatography (silica gel); yield: 0.260g (68%); mp 144C.
3-(3-Chloro-1,2,4-oxadiazol-5-yl)quinuclidine Hydrochloride ( 9 , R1=Cl; R2=Quinuclidin-3-yl):[ 165 ]

A soln of NaNO2 (2.0g, 29mmol) in H2O (1mL) was added dropwise to a soln of the amine 90 (X=NH2; Y=quinuclidin-3yl; 4.0g, 20mmol) in concd HCl (40mL) at 0C. After complete addition, the soln was stirred for 30min and then filtered
and concentrated under reduced pressure. The residue was treated with cold aq K 2CO3and extracted with CH2Cl2. The extracts
were dried and then treated with ethereal HCl to give a white solid; yield: 3.36g (67%); mp 179182C.
13.6.4.2 Addition Reactions

Introductory Text
Addition reactions to the 1,2,4-oxadiazole nucleus are rare and usually involve the complexation of a ring nitrogen by a
metal. The successful isolation of the parent unsubstituted 1,2,4-oxadiazole involves the formation of a complex with
cadmium chloride, from which the parent 1,2,4-oxadiazole is distilled at room temperature and reduced pressure.
[ 13 , 169 ]
Complexes with mercury[ 21 , 161 ] and with several transition metals are also known. [ 22 , 23 ] In a synthetically useful
reaction, the N3 atom of several 1,2,4-oxadiazoles [ 1 6 ] will quaternize, for example the amiloride prodrug 91 forms the
oxadiazolium compound 92 ( Scheme 42 ).[ 170 ]
Scheme 42 Quaternization of a 1,2,4-Oxadiazol-3-amine

with Iodomethane
[ 170 ]
3-Amino-5-(3,5-diamino-6-chloropyrazin-2-yl)-2-methyl-1,2,4-oxadiazol-2-ium Iodide ( 92 , R1=H):[ 170 ]
The pyrazine oxadiazole ( 91 , R1=H; 2.03g, 8.92mmol) was dissolved in dry DMF (20mL) with warming. The resulting
soln was protected from moisture, treated with MeI (10mL), and allowed to stand at 40C overnight to give a yellow solid;
yield: 3.1g (94%); mp 211213C (dec).
13.6.4.3 Modification of Existing Substituents

Introductory Text
The 1,2,4-oxadiazole ring will often have no influence on the chemistry of its substituents. [ 1 6 ] Certain substituents,
however, do have their reactivity altered by the presence of the 1,2,4-oxadiazole ring. For example, the ring is electron
withdrawing, and can behave as a meta-directing group towards aryl substituents at the C3 or C5 positions. [ 21 , 171 , 172 ] The
1,2,4-oxadiazole ring activates -CH and -CCl groups, but there are often differences in reactivity between the 3- and the 5positions (see Sections 13.6.4.3.1 and 13.6.4.3.3). The presence of the 1,2,4-oxadiazole ring also modifies the reactivity of
some nitrogen-containing substituents in the 3- and 5-positions (see Section 13.6.4.3.6). The 1,2,4-oxadiazole ring is often
incorporated into molecules with a view towards investigating the biological activity of the resulting product. Several
methods for such incorporations involve manipulation at the substituent -atom, and therefore important reactions such as
Wittig alkenation at the -carbon (Section 13.6.4.3.5), and the synthesis of 3- and 5-carboxaldehydes, imines, and related
derivatives (Section 13.6.4.3.4) are covered. Carboxylic acid derivatives at the 3- and 5-positions can be manipulated in the
standard way, and this can lead to some 1,2,4-oxadiazoles that are important synthetic intermediates in 1,2,4-oxadiazole
chemistry (see Section 13.6.4.3.2).
13.6.4.3.1 Method 1: Modification of Substituents with an -CH

Introductory Text
5-Methyl substituents on the 1,2,4-oxadiazole ring are readily deprotonated by bases. The resulting anion undergoes a variety
of reactions (see Section 13.6.4.3.1.1).[ 173 176 ] Note that 3-methyl-substituted systems do not deprotonate similarly, but
instead nucleophilic bases add across the 4,5-bond of 3-methyl-1,2,4-oxadiazoles. [ 174 , 175 ] This difference in reactivity can be
accounted for by reference to the respective resonance forms that are available to the anions involved, and by the greater
activation that is available from an adjacent oxygen, as opposed to an adjacent nitrogen. [ 175 ] 5-Methyl-1,2,4-oxadiazoles
( 93 , R2=H) are sufficiently activated to undergo aldol reactions ( Scheme 43 ).[ 21 , 175 , 177 , 178 ] For example, 5-methyl-3phenyl-1,2,4-oxadiazole reacts with benzaldehyde in the presence of zinc chloride to yield a styryl derivative 94 (R1=R3=
Ph; R2=H) in 65% yield.[ 21 , 175 , 178 ] The corresponding 5-ethyl derivative shows reduced activity, producing only a 40%
yield.[ 21 , 175 , 178 ] 5-(Cyanomethyl)-1,2,4-oxadiazoles also undergo reaction with aldehydes. [ 21 , 175 ] The Claisen reaction
between ethyl oxalate and 3-aryl-5-methyl-1,2,4-oxadiazoles 93 (R1=aryl; R2=H) yields the oxo ester substituted 1,2,4oxadiazoles 95 in up to 76% yield.[ 175 , 178 , 179 ]
Scheme 43 Aldol and Claisen Reactions at the C5 Carbon
[ 21 , 175 , 177 179 ]
13.6.4.3.1.1
Variation 1: Deprotonation and Reaction of 5-Alkyl Groups
Introductory Text
Deprotonation of a 5-methyl group on 1,2,4-oxadiazoles is typically achieved with butyllithium at 78 to 70C. The
resulting anion 96 can react with carbonyl compounds or carbon dioxide, [ 173 175 ] or can be trapped with trimethylsilyl
chloride and undergo a subsequent Peterson alkenation (e.g., 98 , Scheme 44 ).[ 173 ] A variety of 3-substituted 5-methyl-1,2,4oxadiazoles undergo deprotonation, followed by nitrosation with isopropyl nitrite, to give 3-substituted 1,2,4-oxadiazol-5aldoximes 97 ( Scheme 44 ).[ 176 ]
Scheme 44 Deprotonation and Reaction at the 5-Methyl

Position
[ 173 176 ]
3-Substituted 1,2,4-Oxadiazole-5-carbaldehyde Oximes ( 97 ); General Procedure:[ 176 ]

BuLi (1 equiv) was added to a soln of the appropriate 5-methyl-1,2,4-oxadiazole dissolved in THF at 70C. The resulting
dark red soln was warmed to 20C over 10min and then cooled to 70C. After 5min, a slight excess of iPrONO was
added, and the soln was warmed to rt. The crude mixture was treated with 3M HCl (25mL) and extracted with Et 2O (350
mL). The combined ethereal extracts were washed with brine (50mL) and then dried (Na 2SO4). Removal of the solvent gave
the crude aldoxime 97 , which was partitioned between Et2O (50mL) and 0.5M NaOH (250mL). The aqueous soln was
adjusted to pH 6 with 3M HCl and extracted with CH 2Cl2 (250mL). The organic soln was then washed with brine (40
mL), dried (Na2SO4), and concentrated on a rotary evaporator. The crude acidic product was further purified by column
chromatography (silica gel).[ 176 ]
13.6.4.3.2 Method 2: Modification of a C3 or C5 Ester Functionality

Introductory Text
Ester functionalities at C3 or C5 of oxadiazoles undergo reactions typical of all esters, [ 4 , 34 , 107 , 165 , 180 , 181 ]and can be converted
by conventional means into carboxylic acids, [ 4 6 , 181 ] hydrazides,[ 34 , 107 , 180 ] and primary amides.[ 34 , 165 ] The amides can, in
turn, be converted into nitriles;[ 34 ] the hydrazides into acid chlorides [ 34 ] and acyl azides;[ 34 , 180 ] the acyl azides into
isocyanates by the Curtius rearrangement; [ 34 , 180 ]and the isocyanates into urethanes, amines, and a variety of other 1,2,4oxadiazol-3-amines.[ 34 , 180 ] The nitriles can be converted into imidates, carboxamides, oximes, and thiocarboxamides. [ 34 ] The
large range of C3 and C5 functionality that is accessible by these methods allows the introduction of a 1,2,4-oxadiazole
moiety into a variety of substrates by standard elaboration of the ester-derived functionality.
13.6.4.3.2.1
Variation 1: Synthesis of 3-Carbonitrile Derivatives
Introductory Text
The conversion of an ester side chain (e.g., of 99 ) into an amide, e.g. 100 , is straightforward. The dehydration of the amide
with phosphoric anhydride allows access to nitriles. This process ( Scheme 45 ) is notable in allowing access to the
extremely useful 5-unsubstituted 1,2,4-oxadiazole-3-carbonitrile 101 .[ 34 ] The nitrile group can easily be converted into a
range of functionalities such as imidates, carboxamides, oximes, and thiocarboxamides. [ 34 ]
Scheme 45 Synthesis of 1,2,4-Oxadiazole-3-carbonitrile
[ 34 ]
1,2,4-Oxadiazole-3-carbonitrile ( 101 ):[ 34 ]
Dry NH3 was passed for 1.5h at 510C through a soln of ethyl 1,2,4-oxadiazole-3-carboxylate ( 99 ; 54.7g, 385mmol) in
EtOH (310mL). The solid was collected by filtration and washed with a little EtOH, leaving the amide 100 ; yield: 36.6g
(84%); mp 174C [THF/benzene (CAUTION: carcinogen)].
The amide (9.7g, 86mmol) and P2O5 (25g, 176mmol) were mixed well, and then heated at 120150C and 0.2Torr for 1.5
h. The nitrile 101 was collected at below 20C. The unchanged amide was mixed with fresh P 2O5, and the procedure was
repeated; yield: (total) 6.1g (75%); bp 145C/760Torr.
13.6.4.3.2.2
Variation 2: Curtius Reaction
Introductory Text
1,2,4-Oxadiazoles substituted with carboxylic acid derivatives are readily available, as discussed above. Conversion via the
hydrazide and into azidocarbonyl-substituted 1,2,4-oxadiazoles 102 can therefore be achieved.[ 34 , 182 ]Curtius rearrangement
of compounds 102 gives the corresponding isocyanates 103 , which, upon further reaction, are converted into a variety of
1,2,4-oxadiazol-3-amines 104 ( Table 8 ). The methodology is illustrated by the synthesis of the urethane derivative 104 (R1
=CO2 t-Bu; R2=H). Subsequent treatment of the urethane 104 (R1=CO2 t-Bu; R2=H) with trifluoroacetic acid gave the
useful and highly desired parent 5-unsubstituted 1,2,4-oxadiazol-3-amine ( 104 , R1=R2=H).[ 34 ]
Table 8 Curtius Rearrangement of Azidocarbonyl 1,2,4-Oxadiazoles[ 34 , 182 ]
1,2,4-Oxadiazol-3-amine ( 104 , R1=R2=H):[ 34 ]
1,2,4-Oxadiazole-3-carbonyl azide[ 34 ] ( 102 , R2=H; 0.046g, 0.33mmol) was added to dry xylene (11mL) containing tBuOH (0.036g, 0.26mmol), and the mixture was heated to 140C during 40min. Evaporation to dryness gave the
intermediate tert-butyl 1,2,4-oxadiazol-3-ylcarbamate ( 104 , R1=CO2 t-Bu; R2=H); yield: 0.061g (quant); mp 8790C.
The carbamate ( 104 , R1=CO2 t-Bu; R2=H; 2.57g, 13.9mmol) was stirred at rt for 1h in TFA (10mL). The solvent was
removed under reduced pressure, and the residue was sublimed at about 60C and 1Torr; yield: 0.53g (45%); mp 112C.
13.6.4.3.3 Method 3: Reactions of Halomethyl-Substituted Oxadiazoles

Introductory Text
Haloalkyl oxadiazoles are available by several of the ring-synthesis methods previously discussed. Thus, the reaction of acid
chlorides with amidoximes[ 108 ] (see Section 13.6.1.1.3.2.4, Table 4 ), or the use of the corresponding anhydrides (see
Section 13.6.1.1.3.2.3, Table 3 ), allows access to chloromethyl-substituted 1,2,4-oxadiazoles. Similarly, the use of suitably
substituted nitriles or amidoximes[ 110 ] allows an efficient entry to the chloro systems (see Section 13.6.1.1.3.3, Scheme 17 ,
and Section 13.6.1.4.1.1, Scheme 30 ).
The halogen of the 5-(halomethyl)-1,2,4-oxadiazoles 105 (X=halo) ( Scheme 46 ) can be replaced, leading to a variety of 5methylene-substituted 1,2,4-oxadiazoles 106 . Clean displacements occur with sulfur (leading to sulfides [ 183 , 184 ] and
thioesters);[ 178 , 185 ] with nitrogen (leading to a range of amines),[ 64 , 96 , 176 , 178 ] and with phenol,[ 96 , 178 ] thiophenol,
[ 96 , 178 ]
thiocyanate,[ 96 , 178 , 183 ] and thiourea.[ 96 , 178 ] The reaction of 5-(chloromethyl)-3-phenyl-1,2,4-oxadiazole with either
potassium carbonate or potassium cyanide in dimethyl sulfoxide does not proceed cleanly, and leads instead to trimeric
products.[ 178 ] The same oxadiazole gives a cyclopropane derivative on treatment with diethyl fumarate in dimethyl sulfoxide.
[ 178 ]
Whereas the reactions of 5-halomethyl substituents are well known in the literature, reports of reactions of 3-halomethyl
substituents are rarer.[ 178 ] Exceptions ( Scheme 46 ) include the reaction of the 3-(chloromethyl)-1,2,4-oxadiazole 105 [R1=
4-HO-3,5-(t-Bu2C6H2)] with amines,[ 64 ] and the Arbuzov reaction between 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole
( 107 , R2=Ph)[ 105 , 173 ] and triethyl phosphite. The latter transformation yields the phosphonate derivative 108 [R2=Ph, R3=
P(O)(OEt)2], and this extremely useful intermediate allows Wittig alkenations at the -carbon; the synthesis of the
phosphonate and its alkenation are dealt with in Section 13.6.4.3.5. The conversion of the chloromethyl functionality into an
aldehyde, or its hydrate, using the Krhnke methodology[ 187] (see Section 13.6.4.3.4) is a useful transformation, and is
applicable to both 3- and 5-(chloromethyl)-substituted 1,2,4-oxadiazoles. [ 186 ] The synthesis and chemistry of these aldehydes
is discussed in Section13.6.4.3.4. The synthesis of polymer-supported 5-(chloromethyl)-1,2,4-oxadiazoles has been reported,
and these have also been shown to undergo displacements of the chlorine atom to furnish a range of polymer-supported 5(aminomethyl)-1,2,4-oxadiazoles. This aspect of 1,2,4-oxadiazole chemistry is discussed in detail in Section 13.6.5.2.
Scheme 46 Substitution of a 3- or 5-Halomethyl

Halogen
[ 64 , 96 , 105 , 173 ,176 , 183 185 ]
2,6-Di-tert-butyl-4-{3-[(dimethylamino)methyl]-1,2,4-oxadiazol-5-yl}phenol Hydrochloride [108 , R2=4HO-3,5-(t-Bu)2C6H2; R3=NMe2]; Typical Procedure:[ 64 ]
A soln of the oxadiazolylphenol 107 [R2=4-HO-3,5-(t-Bu)2C6H2; 4.0g, 12mmol] in DMF (40mL) was treated with excess
Me2NH. The free base was dissolved in EtOH (115mL) and treated with HCl(g). The mixture was evaporated to give an oil
that was then triturated with Et2O to give a solid, which was recrystallized (EtOH/Et 2O); yield: 2.3g (50%); mp 199201C.
13.6.4.3.4 Method 4: Synthesis of 3- and 5-Carbaldehydes, Imines, and Related Derivatives
Introductory Text
The Krhnke methodology[ 186 , 187 ] ( Scheme 47 ) is one method that is available for the synthesis of the 3- or 5carbaldehydes 109 and 112 (from 107 and 111 ) or their hydrates 110 and 113 , respectively. However, the synthetic utility of
such an aldehyde functionality has resulted in the development of other methodologies for the synthesis of 3- and 5carbaldehyde-substituted 1,2,4-oxadiazoles ( Scheme 48 ).[ 176 ] Thus, the 5-carbaldehydes 112 , or their hydrates 113 , are
available from the hydrolysis of nitrones 114 .[ 176 ]
Scheme 48 also illustrates the ozonolysis of the 3- or 5-styryl derivatives 115 or 116 , which provides access to the
aldehydes 109 or 112 , or their hydrates.[ 176 ] A general procedure for the more-versatile ozonolysis route is provided vide
infra. The aldehydes 109 and 112 are easily converted, by standard procedures, into the usual range of derivatives, such as
oximes.[ 176 ] Further elaboration at the -carbon allows the conversion of the oximes into thiocarbohydroximic derivatives
and also into hydroximoyl chlorides, which can be further derivatized. [ 176 , 188 ] Ketone side chains can also undergo
condensation reactions, and this allows access to the usual range of ketone derivatives, such as thiosemicarbazones, oximes,
and dinitrophenylhydrazones. [ 143 , 144 ]
Scheme 47 The Krhnke Route to 3- and 5Carbaldehydes

[ 186 ]
Scheme 48 Other Routes to Aldehyde-Substituted 1,2,4Oxadiazoles

[ 176 ]
Synthesis of 5- or 3-Formyl-Substituted 1,2,4-Oxadiazoles ( 109 / 112 ), or Their Hydrates (110 / 113 );
General Procedure:[ 176 ]
A soln of the appropriate 3- or 5-styryl-1,2,4-oxadiazole ( 115 or 116 ) in CH2Cl2 was cooled to 70C, and treated with
ozone generated by using a Welsbach ozonator. Upon completion of the ozonolysis (as determined by TLC), excess Me 2S
was added, and the reaction was warmed to rt with stirring over 2h. The CH 2Cl2 soln was then washed with H2O (225mL),
dried (Na2SO4), and evaporated to give the desired product, together with PhCHO. The resulting mixture was allowed to
solidify and was washed with CCl4 to remove the residual benzaldehyde. Recrystallization gave the desired aldehyde
( 109 or 112 ) or hydrate ( 110 or 113 ). For example, 3-(4-pyridyl)-1,2,4-oxadiazole-5-carbaldehyde hydrate ( 113 , R1=4pyridyl) was obtained in 72% yield; mp 119120C.
13.6.4.3.5 Method 5: Wittig Reactions at the -Carbon

Introductory Text
The use of the Peterson reaction to allow alkenation at an -carbon on the 5-position of the 1,2,4-oxadiazole ring was
discussed in Section 13.6.4.3.1.1 ( Scheme 44 ). Peterson alkenation at an -carbon on the 3-position is not possible because
of the inactivity of the 3-methyl substituent toward deprotonation (for a more detailed discussion, see Section 13.6.4.3.1).
Thus, to achieve alkenation at the -carbon of the 1,2,4-oxadiazole 3-position, the WadsworthEmmons variation of the
Wittig-type alkenation has been used ( Scheme 49 ).[ 173 ]The requisite phosphonate 117 was generated by Arbuzov reaction of
the corresponding 3-(chloromethyl)-1,2,4-oxadiazole [see Section 13.6.4.3.3 for a discussion relating to the uses of
(chloromethyl)-substituted oxadiazoles]. Deprotonation of phosphonate 117 , and reaction with the protected
ketone 118 gave, after deprotection, the 3-vinyl-1,2,4-oxadiazole 119 , a heterocyclic derivative of the antimicrobial
pseudomonic acid.[173 , 189 ]
Scheme 49 Alkenation at an -Carbon in the 1,2,4Oxadiazole 3-Position
[173 ]
(E)-3-Normonyl-5-phenyl-1,2,4-oxadiazole ( 119 ):[ 173 ]
3-(Chloromethyl)-5-phenyl-1,2,4-oxadiazole (1.65g, 8.5mmol) was dissolved in P(OEt) 3 (2.0mL, 11.6mmol) and refluxed
for 1h. The residue was distilled under reduced pressure to yield the phosphonate 117 ; yield: 1.47g (74%); bp 122125C
(0.5Torr).
To a washed 50% suspension of NaH in oil (48mg, 1.0mmol) in dry THF (10mL) at 0C was added the
phosphonate 117 (296mg, 1.0mmol) in THF (5mL). The cooling bath was removed and the mixture was stirred at rt until
evolution of H2 had ceased, and the soln became homogenous (1h). The soln was cooled to 0C, and the protected
ketone 118 (0.52g, 1.0mmol) was added. The mixture was stirred at 0C for 30min, and then at rt for 1h. The mixture was
quenched with NH4Cl, extracted with EtOAc, dried (MgSO4), and the solvent was removed under reduced pressure. The
resultant oil was taken up in THF/H2O (4:1; 100mL) and treated with concd HCl (10 drops) for 5min. Then the mixture was
quenched with NaHCO3, and extracted with EtOAc, dried (MgSO 4), and the solvent was removed under reduced pressure.
The crude product was purified by chromatography [Merck Kieselgel H (type 60, 5g), 05% MeOH/CH 2Cl2]; yield: 98mg
(22%). The Z-isomer was also obtained; yield: 31mg (7%).
13.6.4.3.6 Method 6: Modification of Nitrogen Substituents

Introductory Text
The conversion of the amino groups in the C3 and C5 positions into diazonium groups and the subsequent nucleophilic
substitution of the diazonium groups is dealt with in Sections 13.6.4.1.4.1 and 13.6.4.1.4.2 (Scheme 41 and Table 8 ). The
(phenyldiazenyl)oxadiazole 121 is obtained ( Scheme 50 ) by the oxidation of the hydrazino derivative 120 , obtained by the
reaction of phenylhydrazine with 5-chloro-2-phenyl-1,2,4-oxadiazole. [ 190 ] The (aryldiazenyl)oxadiazoles can be reduced by
hydrazine in the presence of palladium on charcoal to give the corresponding hydrazino oxadiazoles. [ 190 ]
Scheme 50 Synthesis of (Aryldiazenyl)oxadiazoles
[ 190 ]
Amino substituents on 1,2,4-oxadiazoles often display relatively low nucleophilic character. [ 191 ] For example, reaction with
phenyl isothiocyanate is achieved only with difficulty, [ 191 ] and reaction with methyl iodide can result in methylation of the
N2 ring nitrogen,[ 170 ] rather than reaction at the C3 amino substituent. Imination-type reactions of the exocyclic nitrogen of
1,2,4-oxadiazol-3-amines are, however, well known ( Scheme 51 ).[ 1 5 , 34 , 64 , 191 , 192 ] Such reactions provide access to the
usual range of products, such as Schiff bases,[ 34 ]formamidine derivatives,[ 34 ] and imino ether derivatives. [ 64 , 192 ]
Scheme 51 Conversion of the 3-Amino Group into an

Imino Ether
[ 192 ]
The amine functionality of amino-substituted 1,2,4-oxadiazoles can also be converted into a variety of amine and amide
derivatives by standard transformations. Thus, the C3-amino group can be converted, albeit in low yield, into an acetamide,
[ 64 , 151 , 165 ]
by the standard procedure of reaction with acetic anhydride. Reaction with acetic formic anhydride gives
formamide derivatives in good yields.[ 64 ] The reaction of 1,2,4-oxadiazol-3-amines with 1,3-diketones [ 193 195 ] or -oxo
esters[ 191 ] allows access to 3-(enamino)-1,2,4-oxadiazoles, which are useful in the study of 1,2,4-oxadiazole side-chain
rearrangements.[ 195 ] Interestingly, the reaction of a 1,2,4-oxadiazol-3-amine with cesium fluoroxysulfate, an electrophilic
fluorination reagent, allows the efficient monofluorination of the 3-amino group. [ 196 ] As discussed above, the attempted
alkylation of the C3-amino substituent leads to the alkylation of a ring nitrogen. Therefore, to achieve alkylation on an
exocyclic nitrogen, the reaction with formaldehyde in the presence of sodium cyanoborohydride is used ( Scheme 52 ).[ 64 ]
Scheme 52 Formation of a (Dialkylamino)-Substituted

1,2,4-Oxadiazole
[ 64 ]
2,6-Di-tert-butyl-4-[3-(dimethylamino)-1,2,4-oxadiazol-5-yl]phenol ( 123 ):[ 64 ]
A mixture of the 1,2,4-oxadiazol-3-amine 122 (2.0g, 6.9mmol)[ 64 ] and paraformaldehyde (2.0g, 67mmol) in glacial AcOH
(45mL) was treated over 10min with NaBH 3CN (2.0g, 32mmol). The mixture was stirred at rt for 24h, then cooled to 0C,
and treated cautiously with ice water (250mL). Solid Na 2CO3 was added until the mixture was slightly basic. The mixture
was extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na 2SO4), and evaporated. The
product was recrystallized (MeOH/H2O); yield: 1.0g (46%); mp 135138C.
13.6.5 Solid-Phase Syntheses

Introductory Text
Recent work, published almost simultaneously by Liang and co-workers, [ 197 , 198 ] and Hbert and co-workers,[199 ] has
demonstrated that several of the 1,2,4-oxadiazole syntheses discussed above can be successfully transferred to the solid
phase. These solid-phase methodologies have proved to be useful for the generation of combinatorial libraries of 1,2,4oxadiazoles. A number of solution-phase combinatorial approaches to 1,2,4-oxadiazoles have also been reported, [ 25 , 200 ] each
of which relies upon the synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes (see
Section 13.6.1.1.3.2.1, Scheme 15 ).
13.6.5.1 Method 1: Synthesis from Solid-Supported Esters

Introductory Text
Biftu, Liang, and colleagues have described two approaches, the first of which [ 197 ] uses an acylation reaction on a solid
support, and is based on the solution-phase chemistry developed by the same group [ 24 ] (see Section13.6.1.1.3.2.2). The solidphase process allows access to 1,2,4-oxadiazoles under neutral conditions, but does require heating, so that specialized
equipment is required for the rocking of the reaction tubes at elevated temperature. The second approach, reported by Liang
and co-workers ( Scheme 53 ) overcomes this difficulty by allowing access to 1,2,4-oxadiazoles under basic conditions at
room temperature, with no need for specialized apparatus. [ 198 ] This versatile process relies upon the use of the TentaGel
resin, activated by 4-nitrophenyl chloroformate, to generate the resin-bound isonipecotate-derived ester 124 . Reaction of this
ester with an amidoxime in the presence of sodium ethoxide gives the resin-bound oxadiazoles 126 , via the intermediate Oacyl amidoximes 125 . The required 1,2,4-oxadiazoles 127 are cleaved from the resin with trifluoroacetic acid. This approach
allows the parallel synthesis of a range of 1,2,4-oxadiazoles on a semi-automated Quest 210 (Argonaut Technologies)
synthesizer. Note that this chemistry is a solid-phase version of the approach discussed in
Section 13.6.1.1.3.2.2 ( Scheme 16 ).
Scheme 53 Solid-Phase Synthesis from Supported

Esters
[ 198 ]

3-(4-Tolyl)-5-(4-piperidyl)-1,2,4-oxadiazole Trifluoroacetate ( 127 , R1=4-Tol); Typical Procedure:[ 198 ]
The resin-bound isonipecotate 124 (100mg beads, 0.020.03mmol) was first soaked in CH2Cl2 (1.5mL) for 1015min, after
which a soln of the appropriate N-hydroxy-4-tolylcarboximidamide (510 equiv) and NaOEt (510 equiv) in EtOH (1.5mL)
was added. The reaction tubes were rotated at rt for 3d. Solvents were drained and the beads were thoroughly washed. The
resin-bound oxadiazole 126 was cleaved by two treatments with TFA in CH2Cl2 (1:1; 30min at rt), to give the title compound
as its trifluoroacetate salt; yield: 90%.
13.6.5.2 Method 2: Synthesis Using Resin-Bound Amidoximes Derived from Resin-Bound Nitriles
Introductory Text
This approach[ 199 ] begins with the treatment of the readily available [ 199 ] resin-bound nitriles 128 ( Scheme54 ) with
hydroxylamine hydrochloride to give the corresponding resin-bound amidoximes 129 in quantitative yields. Given the
dominant position of amidoximes as starting materials for the synthesis of 1,2,4-oxadiazoles, this procedure represents a
development with a huge potential significance for the solid-phase synthesis of 1,2,4-oxadiazoles. Reaction of polymersupported 129 with N-protected amino acids 130 in the presence of diisopropylcarbodiimide (DIC) in diglyme, under
carefully optimized conditions (see procedure below), gives the resin-bound 1,2,4-oxadiazoles 132 , via the intermediate Oacyl amidoximes 131 . Deprotection gives the resin-bound, -amino-substituted 1,2,4-oxadiazoles 133 , which can also be
further derivatized on the nitrogen. Cleavage from the solid phase is performed with trifluoroacetic acid or hydrofluoric acid.
The process works well with most of the amino acids used, but fails with extremely hindered amino acids, such as 2-methyl2-aminopropanoic acid and other ,-disubstituted amino acids; the process also fails with glutamine and asparagine
derivatives. The reaction is successful with succinic and glycolic anhydrides, and is readily applicable to aliphatic carboxylic
acids. However, aromatic acids give products of low purity. The chemistry discussed here is a solid-phase version of the
approach discussed in Sections 13.6.1.1.3.2 ( Scheme 14 ) and 13.6.1.1.3.2.1 ( Table 2). A selection of the resin-bound
nitriles 128 and the acylating agents that gave successful reactions is listed in the table that accompanies Scheme 54 .
Scheme 54 Solid-Phase Synthesis from Supported

Nitriles
[ 199 ]
As an extension of this methodology, the polymer-supported amidoxime 129 can also be treated with chloroacetic anhydride
( Scheme 55 ) to give the polymer-supported 5-(chloromethyl)-1,2,4-oxadiazoles 134 . Note that this approach is a solidphase version of the chemistry discussed in Section 13.6.1.1.3.2.3 ( Table 3 ). Chloride is readily displaced from the 5chloromethyl group, allowing access to the polymer-supported 5-(aminomethyl)-1,2,4-oxadiazoles 135 , and providing a
solid-phase example of the chemistry discussed in Section 13.6.4.3.3 ( Scheme 46 ). The polymer-supported 5(aminomethyl)-1,2,4-oxadiazoles 135 can then be further derivatized. The products can be cleaved from the solid phase with
trifluoroacetic acid or hydrofluoric acid.
Scheme 55 Solid-Phase Synthesis of 5-(Chloromethyl)1,2,4-oxadiazoles
[199 ]
Polymer-Supported 1,2,4-Oxadiazoles ( 132 ); General Procedure:[ 199 ]
The resin-bound nitrile 128 was treated with NH2OHHCl and iPr2NEt in diglyme at 85C for 16h to give the
amidoxime 129 in quantitative yield. The resin-bound amidoxime 129 was treated with an acylating agent (such as a
protected amino acid, a carboxylic acid, or an acetic anhydride) together with diisopropylcarbodiimide in diglyme at rt for 1
h. The acylation was driven to completion by heating the mixture at 60C for 16h, washing away the excess reagents, and
heating at 85C in fresh solvent for 6h, to give the polymer-supported 1,2,4-oxadiazole 132 . Deprotection and cleavage
from the resin was achieved with TFA or HF, to give the free oxadiazoles in greater than 95% purity, as determined by
HPLC/MS.[ 199 ]
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Product Class 6 - 1,2,4-Oxadiazoles-Science of Synthesis, 2004 13-6, 127-184

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Science of Synthesis classification: 13.

13.6.1 Synthesis by Ring-Closure Reactions

13.6.1.1 By Formation of One OC and One NC Bond

Method 1: By the 1,3-Dipolar Cycloaddition Reactions of Nitrile Oxides with Nitriles

Table 1 1,2,4-Oxadiazoles by Cycloaddition of Nitrile Oxides to Nitriles[ 47 , 52 55 , 59 ]

Scheme 3 1,2,4-Oxadiazoles by the MukaiyamaHoshino

Variation 2: By Using Nitrile Oxides Generated from Imidoyl Halides (Halooximes)

Scheme 4 1,2,4-Oxadiazoles from Imidoyl Halides and

Method 2: By 1,3-Dipolar Cycloaddition of Nitrile Oxides to Imines, Followed by Aromatization of

Scheme 5 1,3-Dipolar Cycloadditions to Imines, with

13.6.1.1.2 Fragments CNC and NO

Method 1: Via N-Acylamidoximes

Scheme 6 In Situ Formation of N-Acylamidoximes

Variation 1: Via N-Acylamidoximes Derived from the Reaction of Amide Precursors

Scheme 7 1,2,4-Oxadiazoles from Acylamidines and

Variation 2: Via N-Acylamidoximes Derived from Nitriles

Scheme 8 Synthesis from N-Acyl(alkoxy)imides and

Variation 3: Via N-Acylamidoximes Derived from N-Acyl Isothiocyanates

Scheme 9 Reaction of N-Acylthioamides with

Variation 4: Via N-Acylamidoximes Derived from N-Cyano Compounds

Scheme 10 Synthesis of 1,2,4-Oxadiazolamines from

Method 2: By Nitrosation of N-Acyl -Amino Acid Derivatives Bearing Active Hydrogens on a

Scheme 11 Nitrosation of N-Acyl -Amino Acid

13.6.1.1.3 Fragments ONCN and C

Method 1: From an Amidoxime and a Carbonic Acid Derivative

Scheme 12 1,2,4-Oxadiazoles from Carbonic Acid

Variation 1: From an Amidoxime and a Chloroformate

Variation 2: From an Amidoxime and Phosgene

Method 2: From an Amidoxime and a Carboxylic Acid or a Carboxylic Acid Derivative

Scheme 13 Synthesis of 1,2,4-Oxadiazoles from

Variation 1: From an Amidoxime and a Carboxylic Acid

Scheme 15 Direct Reaction of an Amidoxime with a

Table 2 Synthesis of 1,2,4-Oxadiazoles from Carboxylic Acids and Amidoximes by Using

Variation 2: From an Amidoxime and a Carboxylic Acid Ester

Scheme 16 1,2,4-Oxadiazoles from an Ester and an

Variation 3: From an Amidoxime and an Anhydride

Table 3 1,2,4-Oxadiazoles From an Amidoxime and an Acid Anhydride[ 1 6 , 13 , 26 , 27 ,

Variation 4: From an Amidoxime and an Acid Chloride

Table 4 1,2,4-Oxadiazoles from Amidoximes and Acid Chlorides[ 30 , 64 , 94 , 101 , 104

Method 3: From an Amidoxime and a Nitrile Derivative

Scheme 17 1,2,4-Oxadiazoles from Nitriles and

Scheme 18 1,2,4-Oxadiazoles from the Reaction of

Variation 1: From an Amidoxime and an Alkyl or Aryl Nitrile

Variation 2: From an Amidoxime and a Cyanate

Variation 3: From an Amidoxime and a Cyanogen Halide

Method 4: From an Amidoxime and an Orthoformate

Scheme 19 1,2,4-Oxadiazoles from an Amidoxime and an

Method 5: From an Amidoxime and a Cumulene or Heterocumulene

Scheme 20 1,2,4-Oxadiazoles from an Amidoxime and an

Method 6: From an Amidoxime and an Iminium Compound

Scheme 21 1,2,4-Oxadiazoles from an Amidoxime and a

Scheme 22 1,2,4-Oxadiazoles from Chloroiminium

In an interesting intramolecular version of the iminium approach, the 3-(methylsulfanyl)-2-azaprop-3-eniminium

Scheme 23 Intramolecular Ring Closure onto an Iminium

Scheme 24 1,2,4-Oxadiazoles from Imino Ethers and

Scheme 25 1,2,4-Oxadiazoles from Imidic Chlorides or

13.6.1.2 By Formation of One ON Bond

Method 1: From Nitrene Precursors

Table 5 1,2,4-Oxadiazoles from Nitrenes[ 128 132 ]

Variation 1: By Using Nitrenes Derived from N-Acylamidrazones

Scheme 26 Synthesis via Nitrenes Derived from NAcylamidrazones

Variation 2: By Using Nitrenes Derived Ultimately from Trimethylsilyl Azide

Scheme 27 Synthesis via Nitrenes Derived from