Product Class 7: 1,2,5-Oxadiazoles

13.7 Product Class 7: 

1,2,5-Oxadiazoles 

R. M. Paton 

General Introduction 

Previously published information regarding this class of products can be found in 

Houben–Weyl, Vol. E 8c, pp 648–818, and various aspects of their chemistry have been reviewed. 

[1–18] Their nomenclature has evolved since they were first reported in the later 

part of the 19th century. The term furazan, originally proposed by Wolff [19] for the 1,2,5oxadiazole 

skeleton 1 (Scheme 1), was used by CAS until Volume 121, when it was replaced 

by the more systematic name 1,2,5-oxadiazole; similarly, benzofurazan (2) has 

been renamed 2,1,3-benzoxadiazole: the systematic names will be used throughout this 

section. For mainly historical reasons associated with early uncertainty concerning their 

structure, the corresponding N-oxides 3 and 4 acquired a separate nomenclature based on 

the term furoxan, and these names are still in common usage. In the pharmacological and 

biochemical literature, the abbreviations BFZ and BFX are also used for 2,1,3-benzoxadiazole 

(benzofurazan) and 2,1,3-benzoxadiazole 1-oxide (benzofuroxan), respectively. 

1,2,5-Oxadiazoles and their benzo derivatives have a diversity of applications as pharmaceuticals, 

analytical reagents, propellants and explosives, and starting materials in organic 

synthesis. There is no general pattern of toxicity associated with the 1,2,5-oxadiazole 

framework; however, a wide spectrum of biological activity has been reported for 

compounds incorporating this moiety, and various nitro and azido derivatives have explosive 

properties. Appropriate precautions must therefore be taken during their preparation, 

handling, and manipulation. 

Scheme 1 Structures of 1,2,5-Oxadiazole, 2,1,3-Benzoxadiazole, and Their N-Oxides 

N N 

O 

1 

2 

FOR PERSONAL USE ONLY 

N 

O 

N 

N N 

O 

+ 

O − 

13.7.1 Product Subclass 1: 

Monocyclic 1,2,5-Oxadiazoles (Furazans) 

3 

The chemistry of monocyclic 1,2,5-oxadiazoles has been the subject of a recent comprehensive 

review, [18] and fused 1,2,5-oxadiazoles have also been surveyed. [11,12] Although 

1,2,5-oxadiazoles have been known since the 19th century, the parent unsubstituted compound 

1 was not reported until 1964. [20] The structure of 1 has been determined by microwave 

spectroscopy, [21] and its derivatives have been extensively examined by X-ray crystallography. 

The 1,2,5-oxadiazole ring has C 2v symmetry, and is essentially planar with no 

atom more than 0.01 Š from the best plane. The ð-bond orders are typically 70–80% for 

N2-C3 and C4-N5, and 40–50% for C3-C4, values that are consistent with significant ðelectron 

delocalization; in contrast, the O1-N2 and N5-O1 bonds are essentially single 

bonds. The aromaticity of the parent 1,2,5-oxadiazole, as measured by the Bird unified aromaticity 

index (I A = 53), is comparable with that of isoxazole (I A = 52) and 1,2,4-thiadia- 

4 

N 

O 

N 

O − 

+ 

185 

for references see p 214 

R. M. Paton, Section 13.7, Science of Synthesis, 2004 Georg Thieme Verlag KG

zole (I A = 48), but markedly less than that of the sulfur analogue 1,2,5-thiadiazole 

(I A = 104). [22] The mass spectra, NMR, UV, and IR spectra of 1,2,5-oxadiazoles have been discussed 

in several reviews. [6,7,15] 

The fundamental chemical reactivity of the 1,2,5-oxadiazole system has been studied 

in great detail. Thermal and photochemical ring cleavage occurs at the O1-N2 and C3- 

C4 bonds to yield nitrile and nitrile oxide fragments, and products derived from them. In 

most cases the thermal reaction requires temperatures in excess of 2008C, but for ringstrained 

analogues, e.g. acenaphtho[1,2-c][1,2,5]oxadiazole (acenaphthofurazan), [23] lessforcing 

conditions are needed. For alkyl- and aryl-substituted 1,2,5-oxadiazoles, the heterocyclic 

ring shows a low reactivity toward both electrophiles and nucleophiles; however, 

when one of the substituents is a good leaving group, nucleophilic substitution can 

occur, and this provides a useful synthetic route to a range of heteroatom-substituted analogues 

(see Section 13.7.1.3.1). Treatment with strong reducing reagents, such as lithium 

aluminum hydride, can result in ring cleavage and formation of amino-substituted fragments. 

Although the heterocyclic ring is resistant to attack by acid, one of the ring nitrogens 

can be alkylated under forcing conditions; for example, N-methyl-1,2,5-oxadiazolium 

salts are formed on heating with dimethyl sulfate. [24] Whereas 3,4-disubstituted 

1,2,5-oxadiazoles are stable to alkali, the parent 1,2,5-oxadiazole and its monosubstituted 

analogues undergo ring-cleavage reactions. Various 3-heteroallyl-substituted 1,2,5-oxadiazoles 

undergo Boulton–Katritzky rearrangements [10,25] in which the oxadiazole is converted 

into a new five-membered heterocycle bearing a hydroxyiminoalkyl substituent. 

13.7.1.1 Synthesis by Ring-Closure Reactions 

13.7.1.1.1 By Formation of One O-N Bond 

13.7.1.1.1.1 Fragment O-N-C-C-N 

13.7.1.1.1.1.1 Method 1: 

From 1,2-Dione Dioximes 


186 Science of Synthesis 13.7 1,2,5-Oxadiazoles 

The ready accessibility of 1,2-dione dioximes 5 (glyoximes), and the ease with which they 

are dehydrated, has ensured that this is the most widely used route to monocyclic 1,2,5oxadiazoles 

6 (Table 1). The starting materials are usually prepared by oximation of the 

appropriately substituted 1,2-dione with hydroxylamine, or by Æ-nitrosation of an alkyl 

ketone followed by oximation of the resulting 1,2-dione monooxime. 1,2-Dioximes can 

also be prepared by reduction of 1,2,5-oxadiazole 2-oxides. In cases where the oxide is 

more readily accessible than the 1,2,5-oxadiazole [for example, by nitrile oxide dimerization 

(see Section 13.7.3.1.1.1.1) or dehydration of Æ-nitro ketoximes (see Section 

13.7.3.1.2.1.2)], this 1,2,5-oxadiazole 2-oxide fi glyoxime fi 1,2,5-oxadiazole sequence is 

a valuable synthetic strategy, particularly for symmetrically substituted derivatives. Various 

reagents have been used to achieve the dehydration, including acetic, phthalic, and 

succinic acid anhydrides, sulfuric acid, aqueous ammonia, alcoholic sodium hydroxide, 

urea, dicyclohexylcarbodiimide, and phenyliodine(III) diacetate. Phosphoryl chloride 

and thionyl chloride are also used, but in these cases Beckmann rearrangement may 

lead to 1,2,4-oxadiazoles as byproducts. [26] For cyclic 1,2-dione dioximes, which are not 

susceptible to such Beckmann rearrangements, thionyl chloride proves to be a mild and 

selective reagent; for example, thermally labile acenaphtho[1,2-c][1,2,5]oxadiazole can be 

prepared in a high yield by treatment of acenaphthoquinone dioxime with thionyl chloride 

in dichloromethane. [23] Heating glyoximes with silica gel is also reported to give 1,2,5oxadiazoles. 

[27] For monosubstituted and unsubstituted 1,2,5-oxadiazoles, basic dehydrating 

agents must be avoided, as the products are unstable under alkaline conditions. The 

parent 1,2,5-oxadiazole (1), for example, was first synthesized by melting glyoxime with 

succinic anhydride, and allowing the product to distill from the reaction mixture. [20,28] A 


similar approach has proved successful for a variety of monosubstituted analogues. In 

contrast, disubstituted 1,2,5-oxadiazoles are generally more robust, and the full range of 

dehydrating conditions can often be used. The glyoxime dehydration method is compatible 

with a wide variety of substituents, including alkyl, aryl, and hetaryl groups, as well 

as acyl, carboxy, and amino groups; for example, 4-phenyl-1,2,5-oxadiazol-3-amine is 

formed on heating (1Z,2E)-N¢-hydroxy-2-(hydroxyimino)-2-phenylethanimidamide with 

sodium acetate. [29] Representative examples are shown in Table 1, and typical procedures 

involving various dehydrating agents are described. 

Table 1 1,2,5-Oxadiazoles by Dehydration of 1,2-Dione Dioximes [23,28–35] 

R 1 R 2 

O 

R 3 ONO 


13.7.1 Monocyclic 1,2,5-Oxadiazoles (Furazans) 187 

R 1 R 2 

O 

R 1 R 2 

O 

N 

O 

OH 

NH2OH 

R 1 R 2 

HO N N OH 

5 

− H2O 

R 1 R 2 

N N 

O 

R 1 R 2 Conditions Yield (%) Ref 

H H succinic anhydride, melt 57 [28] 

H Ph Ac2O, 1008C, 1 h 87 [28] 

Ph NH2 2 M NaOH, reflux, 1 h 92 [29] 

H CH2OAc SOCl2,CH2Cl2,508C, 1 h 38 [30] 

Me Me succinic anhydride, 150–1708C 64 [31] 

2-furyl 2-furyl aq urea, 808C 58 [32] 

NH2 NH2 NaOH or KOH, 1708C, 2.5 h 50–70 [33,34] 

CF3 4-O2NC6H4 silica gel, 150 8C, 18 h 77 [27] 

KOH, ethylene glycol, 170–190 8C, 2 h 64 [35] 

SOCl 2,CH 2Cl 2, rt, 24 h 55 [23] 

3,4-Dimethyl-1,2,5-oxadiazole (6,R 1 =R 2 = Me); Typical Procedure: [31] 

Reprinted from (Behr; Brent, Organic Syntheses, Collective Volume IV), Copyright (1963), 

p 342, with permission from John Wiley & Sons, Inc. 

Succinic anhydride (100 g, 1.0 mol) and dimethylglyoxime (116 g, 1.0 mol) were heated 

slowly together until the mixture melted (~100 8C) and then at 150–2008C. External cooling 

was required to prevent an initial rapid rise in temperature. After allowing the mixture 

to cool to ~1208C, H 2O (50 mL) was added, and the product was separated by steam distillation. 

The distillate was extracted with Et 2O (2 ” 100 mL), the Et 2O layers were dried (MgSO 4), 

and the product was purified by distillation; yield: 59–63 g (60–64%); bp 154–1598C. 


R. M. Paton, Section 13.7, Science of Synthesis, 2004 Georg Thieme Verlag KG 

6

3-Phenyl-1,2,5-oxadiazole (6, R 1 =H;R 2 = Ph); Typical Procedure: [28] 

Ac 2O (31.2 g, 306 mmol) was added to (hydroxyimino)(phenyl)acetaldehyde oxime (phenylglyoxime; 

50.2 g, 306 mmol) and the mixture was heated at 1008C for 1 h. The AcOH 

formed was removed under reduced pressure, and the residual oil was distilled under a 

vacuum (bp 68–72 8C/0.3 Torr) to give an oil that solidified and was recrystallized 

(MeOH); yield: 39 g (87%); mp 36–36.58C. 

3-(4-Nitrophenyl)-4-(trifluoromethyl)-1,2,5-oxadiazole (6,R 1 =CF 3;R 2 = 4-O 2NC 6H 4); 

Typical Procedure: [27] 

Silica gel (1.23 g; dried at 150–1708C/0.01 Torr) was added to a soln of 5 (R 1 =CF 3;R 2 =4- 

O 2NC 6H 4; 138 mg, 0.5 mmol) in CH 2Cl 2 (10 mL). The mixture was stirred well and evaporated 

to dryness under reduced pressure. The resulting powder was heated at 150 8C for 18 h 

under N 2. Extraction with Et 2O (100 mL), filtration, removal of the solvent, and chromatography 

[silica, hexane/benzene (CAUTION: carcinogen) 3:2] gave an oil; yield: 100 mg 

(77%); bp 808C/5 Torr. 

Acenaphtho[1,2-c][1,2,5]oxadiazole (6, R 1 ,R 2 = Naphthalene-1,8-diyl); Typical Procedure: [23] 

SOCl 2 (3.1 g, 25 mmol) was added to finely powdered acenaphthoquinone dioxime (5.0 g, 

24 mmol) suspended in dry CH 2Cl 2 (20 mL), and the mixture was stirred at 20 8C for 24 h. 

The resulting mixture was poured onto ice and extracted with CH 2Cl 2 (3 ” 25 mL). The extracts 

were dried (MgSO 4) and the solvent was removed (

Scheme 3 Rearrangement of 1-(1,2,4-Oxadiazol-3-yl)alkanone Oximes [10,37,38] 

O 

R 1 

N 

N 

O 

7 

R 2 

13.7.1.2.2 Method 2: 

From Isoxazoles 

NH 2OH 

HO 

N 

HO 

N 

R 1 

N 

O 

8 

R 1 

9 

N 

N 

N 

O 

R 2 

R 2 

H3O + 

R 1 

N N 

O 

10 

N COR2 H 

R 1 NH 2 

N N 

O 

The oximes of 3-acylisoxazoles are more stable than their 1,2,4-oxadiazole counterparts 

described in Section 13.7.1.2.1, and some of the early claims in the literature for the formation 

of 1,2,5-oxadiazoles have proved to be erroneous. In the presence of base, however, 

they may rearrange to (2-oxoalkyl)-1,2,5-oxadiazoles that deacylate under the reaction 

conditions (Scheme 4). [10,25] The corresponding E-oximes can also provide a source of 1,2,5oxadiazoles, 

provided that the E to Z isomerization can be achieved; this may sometimes 

be accomplished by heating with excess hydroxylamine, thus yielding the oxime derivatives 

of the (2-oxoalkyl)-1,2,5-oxadiazoles. Formation of 1,2,5-oxadiazoles by rearrangement 

of 4,5-dihydroisoxazole-3-carbaldehyde oximes has also been reported. [40–42] 

Scheme 4 Rearrangement of 1-(Isoxazol-3-yl)alkanone Oximes [10,25] 

N 

HO 

R 1 

N 

O 

R 2 

R 3 



OH − 

R 1 

R 2 

N N 

O 

13.7.1.3 Synthesis by Substituent Modification 

R 3 

O 

R 1 

N N 

O 

The inherent stability of the 1,2,5-oxadiazole ring permits a wide range of substituent manipulations 

to be performed. These include the replacement of existing substituents by 

nucleophilic substitution, deoxygenation of 1,2,5-oxadiazole 2-oxides to the corresponding 

1,2,5-oxadiazoles, and functional-group transformations on substituents at the 3- and 

4-positions. These methods are extensively used in synthesis, and are discussed below. N- 

Alkylation with dimethyl sulfate [24] and C-H insertion into monosubstituted 1,2,5-oxadiazoles 

by (methoxycarbonyl)carbene generated from methyl diazoacetate [43] have also 

been reported, but these are not widely used synthetic methods. 

11 

R 2 



13.7.1.3.1 Substitution of Existing Substituents 

Nucleophilic substitution reactions occur readily for 1,2,5-oxadiazoles bearing good leaving 

groups, and this approach can afford a range of derivatives not readily accessible by 

the ring-closure methods described in Section 13.7.1.1. Halides, nitrite, and sulfonyl can 

all act as leaving groups, [18] but nitro-1,2,5-oxadiazoles are the most widely used starting 

materials because they are easily accessible. Removal of the exocyclic oxygen of 1,2,5-oxadiazole 

2-oxides is also a powerful route to 1,2,5-oxadiazoles, and Hofmann [44] and Curtius 

[45] degradations of 1,2,5-oxadiazolecarboxamides and 1,2,5-oxadiazolecarbonyl azides 

to the amino derivatives have also been reported. 

13.7.1.3.1.1 Method 1: 

Substitution of Halogens by Nucleophiles 

Although there have been relatively few publications on the displacement of halogens attached 

to the 1,2,5-oxadiazole ring, this approach offers an effective route in cases where 

the halo-1,2,5-oxadiazoles are readily accessible. For example, treatment of 3-chloro-4phenyl-1,2,5-oxadiazole 

with alkoxides gives good yields of the corresponding 3-alkoxy 

compounds. [46] Similarly, 3-alkoxy-4-(3-pyridyl)-1,2,5-oxadiazoles 12 can be prepared by 

the same method (Scheme 5). [47] 

Scheme 5 Substitution of Chloride by Alkoxides [47] 

N 

N N 

O 

Cl NaOR 1 



N 

N N 

O 

12 

OR 1 

13.7.1.3.1.2 Method 2: 

Deoxygenation of 1,2,5-Oxadiazole 2-Oxides 

An efficient route to 1,2,5-oxadiazoles is provided by the deoxygenation of the corresponding 

1,2,5-oxadiazole 2-oxides (Table 2), which can often be efficiently prepared 

through dimerization of nitrile oxides (see Section 13.7.3.1.1.1.1), or by dehydration of Ænitro 

ketoximes (see Section 13.7.3.1.2.1.2). A wide range of substituents can be accommodated, 

but care must be taken to avoid over-reduction. In cases where the target 1,2,5-oxadiazole 

is thermally labile, ring-opened products may also be formed. Several reducing 

agents can be used, including trialkyl and triaryl phosphites, tin(II) chloride/hydrochloric 

acid/acetic acid, and zinc/acetic acid. In some cases, the process may involve reduction to 

the glyoxime and in situ dehydration under the reaction conditions (cf. Section 

13.7.1.1.1.1.1). 


Table 2 Deoxygenation of 1,2,5-Oxadiazole 2-Oxides [48–52] 

R 1 R 2 

N N 

O 

+ 

13 

P(OR 3 ) 3 



R 1 R 2 

− 

O 

N 

O 

6 

N 


Ph Ph P(OEt) 3, 160–1708C, 5 h 93 [48] 

CN CN P(OEt) 3, benzene, 30–408C, 5 h 74 [49] 

Ph CO2Et P(OEt) 3, benzene, 808C, 4 h 45 [49] 

OEt CO2Et P(OEt) 3, benzene, 808C, 3 h 90 [49] 

CO2Et CO2Et P(OEt) 3, benzene, 808C, 1 h 89 [49] 

CONH2 Me P(OMe) 3, reflux, 7 h 62 [50] 

Me CONH2 P(OMe) 3, reflux, 22 h 68 [50] 

Me pyrrolidin-1-yl P(OEt) 3, reflux, 10 h 75 [51] 

4-ClC6H4CO 4-ClC6H4CO Zn, AcOH, Ac2O, 70 min 37 [52] 

4-Methyl-1,2,5-oxadiazole-3-carboxamide (6,R 1 = CONH 2;R 2 = Me); Typical Procedure: [50] 

3-Methyl-1,2,5-oxadiazole-4-carboxamide 2-oxide (13, R 1 = CONH 2; R 2 = Me; 1.0 g, 

7.0 mmol) was refluxed with P(OMe) 3 (23 mL) for 7 h. The mixture was poured into cold 

H 2O (150 mL) containing 10 M HCl (~5 mL) to accelerate the hydrolysis of excess phosphite. 

The aqueous phase was extracted with Et 2O, and the extracts were washed with 

H 2O (2 ”), dried (MgSO 4), and concentrated under reduced pressure. The product was recrystallized 

(H 2O); yield: 0.55 g (62%); mp 1238C. 

3,4-Bis(4-chlorobenzoyl)-1,2,5-oxadiazole (6,R 1 =R 2 = 4-ClC 6H 4CO); Typical Procedure: [52] 

To a stirred mixture of 3,4-bis(4-chlorobenzoyl)-1,2,5-oxadiazole 2-oxide (13, R 1 =R 2 =4- 

ClC 6H 4CO; 2.0 g, 5.5 mmol), AcOH (8.2 g, 136 mmol), and Ac 2O (10 mL) in THF (60 mL) at 

rt was added over 70 min Zn (3.0 g at a rate of 0.2 g every 5 min). The mixture was stirred 

for a further 3.5 h, and the insoluble materials were filtered off and washed with CHCl 3 

(20 mL). The filtrate and the washings were combined and concentrated under reduced 

pressure. The residue was dissolved in CHCl 3 (100 mL), and the soln was neutralized with 

sat. aq Na 2CO 3, washed with sat. aq NaCl, and dried (MgSO 4). The soln was concentrated 

and the residue was purified by chromatography (silica gel, hexane/CHCl 3); yield: 0.7 g 

(37%); mp 94–96 8C. 

13.7.1.3.1.3 Method 3: 

Substitution of Nitrogen by Nucleophiles 

The nitrite anion is an excellent leaving group, and when attached to the 1,2,5-oxadiazole 

ring is readily displaced by a variety of nitrogen, oxygen, sulfur, and carbon nucleophiles 

(Scheme 6). [18] For example, hydroxy-1,2,5-oxadiazoles, alkoxy-1,2,5-oxadiazoles, and aryloxy-1,2,5-oxadiazoles 

15 have been prepared by treatment of mononitro-1,2,5-oxadiazoles 

14 with hydroxides, alkoxides, and phenoxides, respectively. [53–56] Nucleophilic displacements 

by thiocyanates, [57] thiols, [57,58] and active methylene compounds [18] have also 

been reported. The two nitro groups of 3,4-dinitro-1,2,5-oxadiazole can be replaced stepwise; 

thus 1,2,5-oxadiazole derivatives 16 bearing two differently substituted amino 

groups at the 3- and 4-positions can be prepared (Scheme 7). [18] 



Scheme 6 Nucleophilic Substitution Reactions of Nitro-1,2,5-oxadiazoles [53–56] 

R 1 NO 2 

N N 

O 

14 

Nu − 

Nu = OH, OR 2 , SR 2 , NR 2 2, CR 2 3 

R 1 Nu 

N N 

O 

15 

Scheme 7 Nucleophilic Substitution Reactions of 3,4-Dinitro-1,2,5-oxadiazole [18] 

O 2N NO 2 

N 

O 

R 1 2NH 

O 2N 

N N N 

O 

NR 1 2 

R 2 2NH 

R 2 2N 

N N 

O 

4-Phenyl-1,2,5-oxadiazol-3-ol (15,R 1 = Ph; Nu = OH); Typical Procedure: [56] 

A soln of NaOH (0.8 g, 20 mmol) in H 2O (5 mL) was added dropwise with vigorous stirring 

to a soln of 3-nitro-4-phenyl-1,2,5-oxadiazole (14, R 1 = Ph; 1.91 g, 10 mmol) in DME (8 mL). 

The mixture was stirred for 2 h at 708C, diluted with H 2O (50 mL), cooled, and extracted 

with CHCl 3 (30 mL). The aqueous layer was acidified (HCl) and extracted with Et 2O 

(3 ” 50 mL). The combined extracts were dried (MgSO 4), filtered, and concentrated. The 

residue was dissolved in acetone, and H 2O was added to precipitate white prisms; yield: 

1.40 g (86%); mp 177.5–1788C. 

13.7.1.3.2 Modification of Substituents 

The stability of the 1,2,5-oxadiazole nucleus has been exploited for the preparation of 

many complex mono- and bicyclic analogues from readily accessible simple 1,2,5-oxadiazoles. 

[16,18] 

13.7.1.3.2.1 Of Oxygen 

1,2,5-Oxadiazol-3-ols exist mainly as the hydroxy tautomer; they show marked acidic 

properties, and reaction with electrophilic reagents takes place exclusively at the hydroxy 

oxygen. [18] For example, ethers and esters can be prepared by using electrophilic alkylating 

and acylating agents, respectively (Scheme 8). [59,60] An electrophile can, however, 

be introduced at the N2-position of 1,2,5-oxadiazol-3-ols via their O-(trimethylsilyl) derivatives 

(Scheme 9). 

Scheme 8 O-Alkylation and O-Acylation of 1,2,5-Oxadiazol-3-ols [59,60] 

R 1 OH 

R 1 OR 2 

R2X N 

O 

N N 

O 

N 

R 2 = alkyl, acyl 

Scheme 9 N-Alkylation of (Trimethylsiloxy)-1,2,5-oxadiazoles [56] 

R 1 OH 

R 1 OTMS 

N N N N 

O 

O 

R 1 = Ph, CN 

TMSCl, Et3N 



HC(OEt)3 

R 1 O 

N NEt 

O 


16 

+ 

NR 1 2 

R 1 OEt 

N N 

O

13.7.1.3.2.2 Of Sulfur 

In general, 1,2,5-oxadiazolyl sulfides are readily oxidized to the corresponding sulfones 

17 (Scheme 10), the ease of the process being dependent mainly on the nature of the second 

substituent. Typical oxidizing agents include hydrogen peroxide (30–80%) in acetic 

acid, and Caro s acid. [57] 

13.7.1.3.2.3 Of Nitrogen 

Scheme 10 Oxidation of 1,2,5-Oxadiazolyl Sulfides 

to 1,2,5-Oxadiazolyl Sulfones [51,57,58] 

R 

N 

O 

N N 

O 

N 

1 SO2R2 R1 SR2 [O] 

17 

The reactions of 1,2,5-oxadiazolamines have been studied in depth, and the topic has 

been reviewed. [16,18] The examples presented here represent a small portion of the extensive 

literature on the subject; for a more-detailed discussion of synthetic opportunities, 

the reader is referred to the literature cited in the reviews. 1,2,5-Oxadiazol-3-amines 18 

(Scheme 11) are weak bases, and form salts with anhydrous mineral acids only. Alkylation 

does not occur under normal conditions, but may be achieved by lithiation followed by 

treatment with an alkyl halide. [18,61] In contrast, sulfonation and acylation occur more 

readily. Condensation reactions occur readily with aldehydes and ketones; [34,62,63] for example, 

the reaction of 1,2,5-oxadiazole-3,4-diamine with 1,2-diones provides a valuable 

route to [1,2,5]oxadiazolo[3,4-b]pyrazines 19. [16] 

Oxidation reactions have been widely studied. [18] Treatment with peracids yields the 

corresponding nitro compounds 14, [16] and reaction with potassium permanganate/hydrochloric 

acid gives azo-1,2,5-oxadiazoles 20, [64] which can be further oxidized to the corresponding 

azoxy compounds 21. [65] Azido-1,2,5-oxadiazoles undergo the expected 1,3-dipolar 

cycloaddition reactions, for example with alkynes to give 1,2,3-triazole adducts 

22. [66] 

Scheme 11 1,2,5-Oxadiazoles with Nitrogen-Containing Substituents 

R 1 NH 2 

N N 

O 

18 

R 1 N 

N N 

O 

21 

R 1 

R 1 

O 

N N 

N 

O − 

+ 

R 1 



N 

N 

19 

R 2 

N 

O 

N 

N 

N 

N 

R 3 

22 

R 1 N 

R 1 

N N 

O 

N O 

N 

20 

O 

N N 

N 

R 1 



13.7.1.3.2.4 Of Carbon 

The stability of the 1,2,5-oxadiazole ring allows various functional group manipulations 

to be performed on carbon substituents. [15,18] Methyl-1,2,5-oxadiazoles, which are readily 

accessible, e.g. by glyoxime dehydration (see Section 13.7.1.1.1.1.1), provide a rich source 

of functionalized analogues. Treatment with N-bromosuccinimide yields the monobromo 

compounds 23, [67] which undergo a range of nucleophilic substitutions, for example with 

amines, azide, hydroxide, alkoxides, and thiolates (Scheme 12). Whereas condensations 

of the methyl group are not feasible under standard conditions, the electron-withdrawing 

properties of the ring facilitate lithiation at the methyl group. [68] The resulting lithiated 

species 24 reacts readily with electrophiles such as alkyl halides, chlorosilanes, carbonyl 

compounds, and nitriles. Diazo(1,2,5-oxadiazolyl)methanes, which can be prepared from 

the corresponding amines, prove to be valuable precursors of side-chain functionalized 

derivatives; [18] their [1 + 2]-cycloaddition reactions with alkenes affords the expected cyclopropyl-1,2,5-oxadiazoles, 

and [3 + 2] cycloaddition with alkynes and nitriles leads to 

the pyrazolyl and 1,2,3-triazolyl derivatives, respectively. Other side-chain functionalities, 

such as alcohols and amines, react in the expected manner. Aryl-1,2,5-oxadiazoles 

undergo electrophilic substitution in the aryl ring, with the heterocycle exerting an ortho/para-directing 

effect. [69,70] 

Scheme 12 Functionalization of Methyl-1,2,5-oxadiazoles [67,68] 

R 1 

N N 

O 

NBS 

BuLi 



R 1 

N N 

O 

23 

N N 

O 


2,1,3-Benzoxadiazoles (Benzofurazans) and 

Other Annulated 1,2,5-Oxadiazoles 

R 1 

24 

Br 

Li 

Nu − 

E + 

R 1 

N N 

O 

R 1 

N N 

O 

The geometry of the heterocyclic ring in 2,1,3-benzoxadiazoles (benzofurazans) shows 

similar trends to that of the parent 1,2,5-oxadiazole, and there is significant doublebond 

fixation in the fused homocyclic ring. [71] 2,1,3-Benzoxadiazoles are thermally more 

stable than monocyclic 1,2,5-oxadiazoles, but can be cleaved photolytically. [72] Like monocyclic 

1,2,5-oxadiazoles, 2,1,3-benzoxadiazoles are more susceptible to reduction than to 

oxidation. Treatment of 2,1,3-benzoxadiazole (2) with tin and hydrochloric acid affords 

benzene-1,2-diamine, whereas catalytic hydrogenation takes place exclusively in the homocyclic 

ring to give 4,5,6,7-tetrahydro-2,1,3-benzoxadiazole [6, R 1 ,R 2 = (CH 2) 4]. Electrophilic 

substitution, e.g. nitration, occurs preferentially at the 4-position. Halide substituents 

in the homocyclic ring can be displaced by a variety of nucleophiles, and the ease of 

the reaction with amines, thiols, and phenols of 4-halo-7-nitro-2,1,3-benzoxadiazoles and 

4-halo-5,7-dinitro-2,1,3-benzoxadiazoles, in conjunction with the characteristic fluorescence 

exhibited by the resulting derivatives, forms the basis of a powerful analytical technique 

that has found particular application in the biosciences. [73,74] 


Nu 

E


13.7.2.1.1 By Annulation to an Arene 

The main methods for forming the heterocyclic ring of 2,1,3-benzoxadiazoles involve the 

dehydration of benzo-1,2-quinone dioximes and the cyclization of various 1,2-disubstituted 

arenes, including dinitroarenes and 2-azidonitroarenes. 

13.7.2.1.1.1 By Formation of One O-N Bond 

13.7.2.1.1.1.1 Fragment O-N-C-C-N 

13.7.2.1.1.1.1.1 Method 1: 

From Benzo-1,2-quinone Dioximes 

The dehydration of benzo-1,2-quinone dioximes (Scheme 13) proceeds in a similar manner 

to that of their monocyclic counterparts (see Section 13.7.1.1.1.1.1). The approach is 

compatible with a wide range of functionalities in the homocyclic ring, and is also appropriate 

for 1,2,5-oxadiazoles fused to heterocyclic rings. [7,15] Various dehydrating agents 

have been used, including aqueous alkali, thionyl chloride, acetic anhydride, phenyl isocyanate, 

acetyl and benzoyl chlorides, and sulfuric acid. For example, the parent 2,1,3benzoxadiazole 

(2) is formed on steam distillation of an alkaline solution of benzo-1,2quinone 

dioxime. [75] Alternatively, cyclization may be achieved by thermolysis of the diacetate 

or dibenzoate derivatives. [76] 

Scheme 13 2,1,3-Benzoxadiazoles by Dehydration 

of Benzo-1,2-quinone Dioximes [7,15] 

R 1 

OH 

N 

N 

OH 

− H 2O 

R 1 

13.7.2.1.1.1.1.2 Method 2: 

From 2-Azidonitro- and 2-Azidonitrosoarenes, and 2-Azidoanilines 

Various nitro- and nitrosoarenes and -anilines, including 2-azido derivatives generated 

from the 2-haloanilines [77] and 1,2-dinitro compounds, have been used as 2,1,3-benzoxadiazole 

precursors [78,79] (Schemes 14 and 15). Treatment of 2-nitrosophenols with hydroxylamine 

also gives 2,1,3-benzoxadiazole, presumably by an oximation–dehydration pathway 

involving the tautomeric ortho-quinone monooxime. Other related approaches 

include oxidation of 2-nitrosoanilines by using ferricyanide, lead(IV) acetate, [80] or hypochlorite, 

[81] the reduction of 1,2-dinitroarenes with borohydride, and thermolysis of 2-nitroanilines 

and 2-nitroacetanilides. 

N 

O 

N 

Scheme 14 2,1,3-Benzoxadiazoles from 2-Haloanilines [77] 

X 

NH2 R1 R1 X = halo 


13.7.2 2,1,3-Benzoxadiazoles (Benzofurazans)/Other Annulated 1,2,5-Oxadiazoles 195 

NaN3, DMSO 

N 

O 

N 



Scheme 15 2,1,3-Benzoxadiazoles from 1-Halo-2-nitrosobenzenes or 

1,2-Dinitrobenzenes [78,79] 

X = halo 

X 

N3 NaN3 heat 

NO 

R1 R1 NO 

R1 NO2 

− N2 

N3 

NaN3 heat 

− N2 R 

NO2 

1 R1 R 

NO2 

1 

4-Fluoro-2,1,3-benzoxadiazole; Typical Procedure: [77] 

CAUTION: Sodium azide can explode on heating and is highly toxic. 

A soln of NaN 3 (3.91 g, 60 mmol) in DMSO (85 mL) was added dropwise at rt to a stirred 

soln of 2,6-difluoro-1-nitrosobenzene (8.50 g, 59 mmol) in DMSO (85 mL). After 1 h, the 

soln was poured into H 2O. The mixture was extracted with Et 2O, and the extracts were 

dried (Na 2SO 4), concentrated under reduced pressure, and distilled; yield: 5.9 g (72%); bp 

838C/12 Torr. 

2,1,3-Benzoxadiazoles; General Procedure: [78] 


A mixture of the 1,2-dinitroarene and NaN 3 (1:2 molar ratio) in ethylene glycol was heated 

at 120–1508C until gas evolution ceased. The mixture was poured into H 2O and extracted 

with Et 2O. The extracts were dried (Na 2SO 4) and concentrated under reduced pressure, 

and the residue was recrystallized (EtOH); yield: 24–78%. 

13.7.2.1.2 By Annulation to the Heterocyclic Ring 

Although 2,1,3-benzoxadiazoles are not prepared by annulation to a preformed 1,2,5-oxadiazole 

ring, the reactions of appropriate substituents at the 3- and 4-positions of 1,2,5oxadiazoles 

can provide an efficient route to hetareno-fused analogues, thus providing 

an alternative to the methods described above. For example, the condensation reactions 

of 1,2,5-oxadiazole-3,4-diamine with Æ-dicarbonyl compounds have been extensively used 

to prepare [1,2,5]oxadiazolo[3,4-b]pyrazines, [16] whereas [1,2,5]oxadiazolo[3,4-c]pyridines 

25 have been prepared by treatment of 3,4-diaroyl-1,2,5-oxadiazoles with alkylamines 

(Scheme 16). [52,82,83] 

Scheme 16 Synthesis of [1,2,5]Oxadiazolo[3,4-c]pyridines from 

3,4-Diaroyl-1,2,5-oxadiazoles [52,82,83] 

Ar 1 

O 

O 

N N 

O 

Ar 1 



R 1 NH2 

R 1 

N 

Ar 1 

Ar 1 

25 

N 

O 

N 

NaN3 

N 

O 

N 

N 

O 

N 

O − 

+ 


R 1 

N 

O 

N

Ethyl 4,7-Bis(4-chlorophenyl)[1,2,5]oxadiazolo[3,4-c]pyridine-6-carboxylate 

(25,Ar 1 = 4-ClC 6H 4;R 1 =CO 2Et); Typical Procedure: [52] 

A mixture of 3,4-bis(4-chlorobenzoyl)-1,2,5-oxadiazole (4.0 g, 11.5 mmol) and ethyl glycinate 

hydrochloride (18.0 g, 129 mmol) in BuOH (200 mL) was refluxed for 24 h. The mixture 

was concentrated under reduced pressure, and CHCl 3 (200 mL) was added. The soln 

was washed with aq HCl (3 ” 100 mL) and H 2O, dried (MgSO 4), and concentrated under reduced 

pressure. The residue was purified by chromatography (silica gel, hexane/CHCl 3); 

yield: 4.0 g (84%); mp 125–1278C. 

13.7.2.2 Synthesis by Ring Transformation 

The Boulton–Katritzky rearrangement of some benzo-fused heterocycles bearing an adjacent 

nitroso group can afford 2,1,3-benzoxadiazoles (Scheme 17). [84] This approach has 

been little utilized, with rare examples including the conversion of 4-nitroso-2,1,3-benzoxadiazole 

1-oxides into 4-nitro-2,1,3-benzoxadiazoles, [85] and the formation of 4-acetyl- 

2,1,3-benzoxadiazoles from 3-methyl-7-nitroso-2,1-benzisoxazoles generated in situ by 

phosphite-mediated reduction of the 7-nitro compound. [86] 

Scheme 17 Rearrangement of 4-Nitroso-2,1,3-benzoxadiazole 

1-Oxides and 3-Methyl-7-nitroso-2,1-benzisoxazoles [84] 

X O 

N 

X O 

N 

R1 R1 O 

X = N(O), C(Me) 

N 

O 

N 



13.7.2.3.1.1 Method 1: 

Substitution of Hydrogen 


13.7.2 2,1,3-Benzoxadiazoles (Benzofurazans)/Other Annulated 1,2,5-Oxadiazoles 197 

The easiest electrophilic substitution reaction is nitration. [7] 2,1,3-Benzoxadiazole reacts 

preferentially at the 4-position, and a second nitro group can sometimes be inserted at 

C6; 4- and 5-substituted analogues are nitrated at C7 and C4, respectively. Other electrophiles 

generally react less readily, nitrosation and diazo coupling occurring only in the 

presence of activating groups. Halogens react to give addition and/or substitution products. 

[87] 2,1,3-Benzoxadiazole-4-carbaldehyde can be prepared by treatment of 2,1,3-benzoxadiazole 

with lithium diisopropylamide followed by dimethylformamide. 

13.7.2.3.1.2 Method 2: 


Halides are displaced by a variety of nucleophiles, including alkoxides, phenoxides, thiolates, 

cyanide, and amines. [7] 4-Halo-2,1,3-benzoxadiazoles give 4- or 5-substituted products 

resulting from normal ipso or cine reactions (Scheme 18), and 5-halo derivatives react 

similarly. Nucleophilic attack is greatly enhanced when the ring is further activated by 

nitro substituents; thus 4-chloro-7-nitro compounds react rapidly with phenols, amines, 

or thiols to give the 4-substituted 7-nitro derivatives. The 5,7-dinitro analogues are even 



more reactive. [88] The nitro groups in 4,6-dinitro-2,1,3-benzoxadiazole can be substituted 

by chloride or azide. 

Scheme 18 Nucleophilic Substitution Reactions of 

4-Halo-2,1,3-benzoxadiazoles [7] 

R 1 

X 

N 

O 

N 

NuH 

X = F, Cl, Br; Nu = OAr 1 , NR 2 2, SR 2 


R 1 

Nu 

N 

O 

N 

13.7.2.3.2.1 Method 1: 

Deoxygenation of 2,1,3-Benzoxadiazole 1-Oxides 

The partial reduction of 2,1,3-benzoxadiazole 1-oxides 26 (X = C) is an efficient and widely 

used route to a wide range of 2,1,3-benzoxadiazoles 27 (X = C) and their heterocyclic annulated 

analogues (Table 3). The conversion can be achieved either directly by deoxygenation 

with a tervalent phosphorus compound (usually a trialkyl phosphite) [89–93] or in 

two stages via the dioxime, with subsequent in situ dehydration using hydroxylamine/alkali 

[94,95] or sodium azide. [78,79] 

Table 3 Deoxygenation of 2,1,3-Benzoxadiazole 1-Oxides and Derivatives [78,79,89–95] 

R 2 

R 3 

R 1 

X 

R 4 

26 

N 

O 

N 

O − 

+ 



P(OR 5 ) 3, NH 2OH/NaOH, or NaN 3 

R 2 

R 3 

R 1 

X 

R 4 

27 

N 

O 

N 

R 1 R 2 R 3 R 4 X Conditions Yield (%) Ref 

H Cl H H C P(OEt) 3, EtOH, reflux, 0.5 h 60 [89] 

H Cl Cl H C P(OMe) 3, MeOH, reflux, 2 h 69 [90] 

Cl H Cl H C P(OMe) 3, MeOH, reflux, 2 h 55 [90] 

Cl H H Cl C P(OMe) 3, MeOH, reflux, 2 h 85 [90] 

H CO2Et H H C P(OEt) 3, EtOH, reflux, 3 h 78 [91] 

– Me CH=CH-CH=CH N P(OMe) 3, reflux, 5 h 62 [92] 

H H H H C Ph3P, EtOH, reflux, 0.5 h 68 [93] 

H OMe H H C NH2OH, EtOH, aq NaOH 75 [94] 

O(CH2) 4O H H C NaN3, ethylene glycol, 

140–1508C, 2 h 

75 

[79] 

2,1,3-Benzoxadiazoles 27 (X = C) by Deoxygenation of 2,1,3-Benzoxadiazole 1-Oxides 

(X =C); General Procedure: [78] 

A mixture of the 2,1,3-benzoxadiazole 1-oxide 26 (X = C; ~2.0 g), NaN 3 (molar ratio 1:1), 

and ethylene glycol (40 mL) was heated at 120–1508C until evolution of gases (N 2 and 


N 2O) had ceased (1–2 h). The soln was poured into H 2O(~500 mL) and extracted with Et 2O 

or CHCl 3. The combined extracts were dried (Na 2SO 4) and concentrated under reduced 

pressure, and the residue was recrystallized (EtOH); yield 40–75%. 

5-Methoxy-2,1,3-benzoxadiazole (27,R 1 =R 3 =R 4 =H;R 2 = OMe; X = C); Typical Procedure: [94] 

To a soln of 5(6)-methoxy-2,1,3-benzoxadiazole 1-oxide (5.0 g, 30 mmol) in EtOH (75 mL) 

was added NH 2OH•HCl (7.5 g, 108 mmol) dissolved in the minimum amount of H 2O. Aq 

NaOH (25%) was added to the mixture until gas evolution ceased. After removal of the 

EtOH by distillation, the residue was made alkaline and steam distilled; yield: 3.4 g 

(75%); mp 988C. 

5,6-Dichloro-2,1,3-benzoxadiazole (27,R 1 =R 4 =H;R 2 =R 3 = Cl; X = C); Typical Procedure: [90] 

A soln of 5,6-dichloro-2,1,3-benzoxadiazole 1-oxide (15.0 g, 73 mmol) in MeOH (200 mL) 

and P(OMe) 3 (50 mL) was refluxed for 2 h. The solvent and excess P(OEt) 3 were removed 

under reduced pressure. The residue was steam distilled and recrystallized (EtOH); yield: 

9.5 g (69%); mp 86–87 8C. 


Monocyclic 1,2,5-Oxadiazole 2-Oxides (Furoxans) 

Although 1,2,5-oxadiazole 2-oxides (furoxans) have been the subject of intensive investigation 

for many years, [1,6,9,17] it was not until 1994 that the parent compound 3 was synthesized 

and its structure determined. [96] X-ray crystallography has been extensively used in 

establishing the structures of 1,2,5-oxadiazole 2-oxide (3) and its derivatives. As in 1,2,5oxadiazoles, 

the oxadiazole ring is nearly planar, but the exocyclic oxygen at N2 causes a 

significant distortion, resulting in long O1-N2 and short N2-O bonds; C3-C4 shows 

~30% double-bond character. The effect of the N-oxide moiety in 1,2,5-oxadiazole 2-oxide 

is to reduce the aromatic character of the ring (I A = 35) compared with 1,2,5-oxadiazole 

(I A = 53). [21] The spectroscopic properties of 1,2,5-oxadiazole 2-oxides are discussed in reviews. 

[6,7,15] 

Ring–chain tautomerism between the 2-oxides and 5-oxides is an important feature 

of 1,2,5-oxadiazole 2-oxide chemistry, and is believed to involve (Z)-1,2-dinitrosoalkenes 

as intermediates (Scheme 19). The rate of equilibration and the balance of the equilibrium 

depends on the substituents present; for most monocyclic 1,2,5-oxadiazole 2-oxides, the 

isomers can be separated at room temperature, and heating is required to achieve conversion. 

Thermolysis of monocyclic 1,2,5-oxadiazole 2-oxides in solution [40] or by flash-vacuum 

pyrolysis [97,98] results in ring cleavage at O1-N2 and C3-C4 forming two nitrile oxide 

fragments; in solution, temperatures in excess of 1508C are usually required, but for ringstrained 

analogues and for derivatives bearing bulky substituents, less-forcing conditions 

are needed. 

Scheme 19 Ring–Chain Tautomerism of 1,2,5-Oxadiazole 2-Oxides 

R 1 

+ N 

−O 

N 

O 

R 2 


13.7.3 Monocyclic 1,2,5-Oxadiazole 2-Oxides (Furoxans) 199 

R 1 

ON 

R 2 

NO 

R 1 R 2 

N 

O 

N + 

O − 

The 1,2,5-oxadiazole 2-oxide ring is markedly resistant to electrophilic attack, and reaction 

normally takes place at the substituents. The heterocyclic ring is also resistant to oxidation 

except under forcing conditions. Attack by reducing agents, however, occurs 

more readily to give 1,2,5-oxadiazoles, 1,2-dioximes, 1,2-diamines, or aminomethyl fragments 

depending on the reaction conditions. Nucleophilic substitution reactions at both 

C3 and C4 have been the subject of intensive study; [17] the nitro group is readily displaced 



y, for example, alkoxides, thiols, azides, and amines. The C=N + -O – unit can show nitrone-like 

behavior, reacting as the 4ð-component in various 1,3-dipolar cycloaddition reactions. 

[40,99] Monocyclic 1,2,5-oxadiazole 2-oxides can be transformed into a variety of 

other heterocyclic systems, including isoxazolines, isoxazoles, pyrazolines, and 1,2,5-oxadiazoles. 

[6] For example, 3-methyl-1,2,5-oxadiazole 2-oxides, on heating in alcoholic potassium 

hydroxide, undergo Angeli s rearrangement to form 4-(hydroximino)-4,5-dihydroisoxazoles, 

and (1-nitroalkyl)-1,2,5-oxadiazoles are formed by the Boulton–Katritzky rearrangement 

of the oxime derivatives of 4-acyl-1,2,5-oxadiazole 2-oxides. 

The potential pharmaceutical applications of 1,2,5-oxadiazole 2-oxides continue to 

be a focus of attention; [100] for example, it has recently been established that various 

1,2,5-oxadiazole 2-oxides can act as nitrous oxide prodrugs. [101] 

1,2,5-Oxadiazole 2-oxides are not formed by direct oxidation of 1,2,5-oxadiazoles, but 

they can readily be prepared by ring-closure or cycloaddition pathways. The most synthetically 

useful routes are oxidative cyclization of 1,2-dione dioximes, the dehydration of Ænitro 

ketoximes, and, for symmetrically substituted 1,2,5-oxadiazole 2-oxides, dimerization 

of nitrile oxides. For nonsymmetrically substituted analogues, care must be taken 

in selecting the route and reaction conditions to avoid the formation of mixtures of 2and 

5-oxides. 


13.7.3.1.1 By Formation of One O-N and One C-C Bond 

13.7.3.1.1.1 Fragments O-N-C and N-C 



13.7.3.1.1.1.1 Method 1: 

By Dimerization of Nitrile Oxides 

In view of the synthetic scope of their 1,3-dipolar cycloaddition reactions, the chemistry 

of nitrile oxides 30 has been the subject of intensive study. [102] In the absence of a dipolarophile, 

however, nitrile oxides readily dimerize, thus providing a general route to symmetrically 

disubstituted 1,2,5-oxadiazole 2-oxides 31. In most cases, the reaction occurs 

spontaneously at ambient temperature, so that isolation of the nitrile oxide is difficult. 

The rate of dimerization is substituent dependent; generally, bulky groups slow the process, 

but even 2,4,6-trimethylbenzonitrile oxide [103] and adamantane-1-carbonitrile oxide 

[104] form the expected 1,2,5-oxadiazole 2-oxides on warming. It is usual therefore to 

generate the nitrile oxide from an appropriate precursor in an inert solvent and to allow 

it to dimerize in situ. This approach is not suitable for methylidyneazane oxide (fulminic 

acid; 30, R 1 = H), which yields polymers rather than the parent 1,2,5-oxadiazole 2-oxide, 

nor is it generally appropriate for bicyclic 1,2,5-oxadiazole 2-oxides; a few examples of intramolecular 

dimerization have been reported [105,106] but difunctional nitrile oxides usually 

polymerize to form 1,2,5-oxadiazole 2-oxide polymers. Rearrangement to isocyanates 

[107] competes with the bimolecular dimerization, with the former pathway becoming 

dominant at elevated temperatures (usually >100 8C). The preparation of 1,2,5-oxadiazole 

2-oxides from nitrile oxides is therefore carried out in concentrated solutions at ambient 

temperature. Dimerization to 1,2,4-oxadiazole 4-oxides [108] and 1,4,2,5-dioxadiazines 

[109] has also been observed, but these are exceptional cases, and 1,2,5-oxadiazole 2oxide 

formation is the usual mode of reaction. Although nitrile oxides have been invoked 

as intermediates in numerous reactions, the principal sources, from a synthetic point of 

view, are oximes, hydroximoyl halides 28, nitrolic acids 29 or their precursors, or nitroalkyl 

compounds (Scheme 20). Some representative examples are given in Table 4. 


Scheme 20 Dimerization of Nitrile Oxides [102–109] 

H 

R 1 N 

NO 2 

R 1 N 

29 

R1 Cl 

OH 

N 

OH 

OH 

− 2H 

− HNO2 

− HCl 

28 

R N 

1 O − 

+ 

− H2O 

30 

R 1 NO 2 

R 1 R 1 

N 

O 

31 

N + 

O − 

Table 4 Dimerization of Nitrile Oxides to 1,2,5-Oxadiazole 2-Oxides [108,110–120] 

R 1 Precursor a Conditions Yield (%) Ref 

Ph R1CH2NO2 PhNCO, Et3N, Et2O, reflux, 2 h 82 [111] 

4-ClC6H4 R1CCl=NOH Et3N, benzene, rt, 12 h 46 [108] 

Et R1CH2NO2 PhNCO, Et3N, Et2O, reflux, 2 h 93 [111] 

Bz R1COMe HNO3,558C, 1 h 60 [112] 

Ac R1COMe N2O4, 0–50 8C 93 [113] 

CO2Et R1CH(NO) 2- 

CO2Et Decalin, 1708C, 20 h 75 [114] 

2-thienylcarbonyl R 1 COMe HNO 3, NaNO 2, AcOH, 90–1008C 80 [115] 

Cl R 1 CCl=NOH PhNMe 2,Et 2O, 25 8C, 5 d 97 [116] 

SO 2Ph R 1 CH 2NO 2 90% HNO 3, AcOH, 60–658C, 1 h 85 [117] 

AcO 

O 

O 

OAc 

N 

O 

OAc 

Ph 

N N 

OMe 

OAc 

a See Scheme 20. 



R 1 CH 2NO 2 4-ClC 6H 4NCO, Et 3N, toluene, rt, 18 h 48 [118] 

R 1 COMe HNO 3,H 2SO 4,508C, 5 h 72 [119] 

R 1 CCl=NOH Et 3N, Et 2O, rt, 16 h 95 [120] 

R 1 CH=NOH 5% aq NaOCl, CH 2Cl 2,208C, 12 h 75 [120] 

R 1 CH 2NO 2 

2,4-diisocyanatotoluene, Et 3N, 

toluene, reflux, 7 d 

90 

[120] 





b13.7.3.1.1.1.1.1 Variation 1: 

From Nitrile Oxides Generated from Oximes and Hydroximoyl Halides 

The route to 3,4-diphenyl-1,2,5-oxadiazole 2-oxide (31, R 1 = Ph), originally reported more 

than a century ago, [121] which involves the chlorination of benzaldehyde oxime followed 

by base-induced dehydrochlorination of the resulting hydroximoyl chloride, remains a 

widely applicable method for the synthesis of 1,2,5-oxadiazole 2-oxides. Although various 

hydroximoyl halides can be prepared by direct halogenation of aldoximes, this procedure 

is limited by the range of compatible substituents; alternative milder reagents in common 

use include nitrosyl chloride, [122] N-chlorosuccinimide, [123] N-bromosuccinimide, [124] 

and iodosylbenzene. [125] The dehydrohalogenation step, which was originally carried out 

with sodium hydroxide or aqueous sodium hydrogen carbonate, is now usually performed 

by using triethylamine, the resulting triethylamine hydrochloride being removed 

by filtration and/or washing with water. Alternative hydrohalide scavengers include molecular 

sieves [126] or potassium fluoride. [127] Microwave irradiation has been reported to accelerate 

the formation of ethyl (oxidoazanylidyne)acetate (30, R 1 =CO 2Et) from ethyl 

chloroximidoacetate in the presence of alumina. [128] Some hydroximoyl halides prove difficult 

to isolate, and others are toxic, e.g. as skin irritants, and it is, therefore, common 

practice in these cases to halogenate by using N-chlorosuccinimide or N-bromosuccinimide, 

and then to carry out the dehydrohalogenation–dimerization in situ by addition 

of triethylamine or pyridine. Other reagents that allow one-pot halogenation–dehydrohalogenation–dimerization 

include hypohalites, [129,130] 1-chlorobenzotriazole [131] and 

Chloramine-T. [132] Oxidation of aldoximes to nitrile oxides and thus 1,2,5-oxadiazole 2-oxides 

has also been accomplished by using mercury(II) acetate, [133] dimethyldioxirane, [134] 

or lead(IV) acetate. [135] 

3,4-Bis(4-chlorophenyl)-1,2,5-oxadiazole 2-Oxide (31, R 1 = 4-ClC 6H 4); Typical Procedure: [108] 

A soln of 4-chlorobenzohydroximoyl chloride (5.0 g, 32 mmol) and Et 3N (5 mL) in benzene 

(50 mL) (CAUTION: carcinogen) was kept at 20 8C for 12 h. The precipitated Et 3N•HCl was 

separated by filtration, and the excess base was removed by washing with aq HCl. The solvent 

was removed under reduced pressure to give the product, which was recrystallized 

(EtOH); yield: 2.0 g (46%); mp 143–144 8C. 

13.7.3.1.1.1.1.2 Variation 2: 

From Nitrile Oxides Generated from Nitrolic Acids and Their Precursors 

1,2,5-Oxadiazole 2-oxides can be prepared by thermal or base-induced elimination of nitrous 

acid from nitrolic acids 29, via the corresponding nitrile oxides. [113] Nitrolic acids are 

also probable intermediates in the formation of diacyl-1,2,5-oxadiazole 2-oxides through 

the reaction of methyl ketones with nitrosating or nitrating agents. [136] The mild conditions 

and the ready availability of the starting materials makes this an attractive method. 

Thus, a wide variety of aliphatic, [113,137] aromatic, [52,112,138,139] and heterocyclic [115,119,140,141] 

methyl ketones are converted into the corresponding diacyl-1,2,5-oxadiazole 2-oxides on 

treatment with nitric acid/sodium nitrite or dinitrogen tetroxide. Similarly, the reaction 

of bromomethyl compounds with sodium nitrite/dimethylformamide also gives 1,2,5oxadiazole 

2-oxides via the nitrolic acids. [142,143] 

3,4-Bis(4-ethoxybenzoyl)-1,2,5-oxadiazole 2-Oxide (31,R 1 = 4-EtOC 6H 4CO); 


A mixture of NaNO 2 (0.6 g, 8.7 mmol) and HNO 3 (d = 1.38; 8 mL) in AcOH (16 mL) was added 

to a stirred soln of 1-(4-ethoxyphenyl)ethanone (6.56 g, 40 mmol) in AcOH (8 mL) at rt. After 

heating for 11 h at 608C, the precipitated solids were separated by filtration, washed 

with cold MeOH, and recrystallized (MeOH); yield: 3.65 g (56%); mp 131–1348C. 


13.7.3.1.1.1.1.3 Variation 3: 

From Nitrile Oxides Generated from Nitroalkyl Compounds 

Nitrile oxides are readily generated by dehydration of primary nitro compounds and, in 

the absence of a dipolarophile, usually dimerize to the 1,2,5-oxadiazole 2-oxide. A wide 

range of dehydrating agents have been used, including mono- and diisocyanates (e.g., 

phenyl isocyanate [111] and tolylene diisocyanate [120,144] ), phosphoryl chloride, [145] acid chlorides 

[146] and anhydrides, [147] methyl chloroformate, [148] 4-toluenesulfonic acid with [128] and 

without [149] microwave radiation, di-tert-butyl dicarbonate, [150] 4-toluenesulfonyl chloride/ 

potassium carbonate/18-crown-6, [151] and nitric acid. [117] Nitrile oxides and hence 1,2,5oxadiazole 

2-oxides can also be generated from nitromethyl compounds via nitronate esters. 

[152] Thermolysis of dialkyl nitromalonates affords 3,4-bis(alkoxycarbonyl)-1,2,5-oxadiazole 

2-oxides in good yield. [114] 

3,4-Diphenyl-1,2,5-oxadiazole 2-Oxide (31, R 1 = Ph); Typical Procedure: [111] 

To an ice-cooled soln of PhCH 2NO 2 (15.0 g, 110 mmol) and PhNCO (25 g, 210 mmol) in dry 

Et 2O (50 mL) was added 10 drops of Et 3N. The mixture was shaken at rt for 1 h and then 

refluxed for 1 h. The precipitated PhNHCONHPh was removed by filtration, the Et 2O layer 

was washed with H 2O and dried (MgSO 4), and the solvent was removed under reduced 

pressure; yield: 10.7 g (82%); mp 114.5–115.58C. 

13.7.3.1.2 By Formation of One O-N Bond 

13.7.3.1.2.1 Fragment O-N-C-C-N 

13.7.3.1.2.1.1 Method 1: 

From 1,2-Dione Dioximes 



The most commonly used approach to monocyclic 1,2,5-oxadiazole 2-oxides involves oxidative 

cyclization of 1,2-dione dioximes (Table 5). Various oxidizing agents have been 

used [15] including hypohalites, potassium ferricyanide, nitric acid, nitrogen oxides, 

lead(IV) acetate, manganese(IV) oxide, N-iodosuccinimide, and phenyliodine(III) bis(trifluoroacetate). 

The unsubstituted parent 1,2,5-oxadiazole 2-oxide, which had proved elusive 

for so many years, was first prepared by this approach by using dinitrogen tetroxide 

as the oxidizing agent. [96] In some cases, the ring closure can be accomplished stereospecifically, 

providing access to the individual 2- and 5-oxide isomers for unsymmetrically 

substituted 1,2,5-oxadiazole oxides; [6,15] for example, ferricyanide oxidation of the Z,E-isomer 

of 4-methoxybenzil dioxime (32, R 1 = Ph; R 2 = 4-MeOC 6H 4) affords the corresponding 

1,2,5-oxadiazole 2-oxide 33 (R 1 = Ph; R 2 = 4-MeOC 6H 4). [110] In most cases, however, a mixture 

of the two isomers is formed. The route is compatible with a wide range of functional 

groups and, by choosing the appropriate reagent, alkyl-, aryl-, hetaryl-, amino-, halo-, nitro-, 

and (alkylsulfanyl)-substituted derivatives can be prepared. This approach is also suitable 

for the construction of 1,2,5-oxadiazole 2-oxides fused to other carbocyclic and heterocyclic 

rings. Representative examples are listed in Table 5. 



Table 5 1,2,5-Oxadiazole 2(5)-Oxides by Oxidation of 1,2-Dione Dioximes [96,110,153–160] 

R 1 R 2 

N 

OH 

N 

32 

OH 

[O] 

R 1 R 2 

N 

O 

33 

N + 

O − 


H H N2O4,CH2Cl2, 35–388C, 1 h 45 [96] 

H Ph N2O4,Et2O, 0–208C 71 [153] 

Bn Bn 5% aq NaOCl, EtOH/aq KOH, 

0–20 8C, 20 min 

95 [154] 

(CH 2) 3 8% aq NaOCl, –58C, 15 min 73 [155] 

Ph Ph 8% aq NaOCl, rt 97 [156] 

Ph 4-MeOC 6H 4 aq NaOCl 100 [110] 

Ph NH 2 HCl, Br 2,H 2O, 0–58C 82 [157] 

N(t-Bu)CH 2CH 2N(t-Bu) K 3[Fe(CN) 6], aq KOH, rt 98 [158] 

Cl Me N 2O 4,Et 2O, 0–58C, 19 h 40 [159] 

Ph SPh N 2O 4,CH 2Cl 2, rt, 1 h 90 [160] 

3,4-Diphenyl-1,2,5-oxadiazole 2-Oxide (33, R 1 =R 2 = Ph); Typical Procedure: [156] 

To a soln of benzil dioxime (32,R 1 =R 2 = Ph; 15.0 g, 63 mmol) in 4% aq NaOH was added 8% 

aq NaOCl (350 mL). The resulting precipitate was filtered off, washed with H 2O, dried, and 

recrystallized (EtOH); yield: 14.5 g (97%); mp 118 8C. 

13.7.3.1.2.1.2 Method 2: 

From Æ-Nitro Ketoximes 



Formation of 1,2,5-oxadiazole 2-oxides by nitrosation/nitration of alkenes has been 

known since the late 19th century, [161] and has since been developed into an efficient 

route for some analogues not readily accessible by other means. [162,163] For example, it is 

of particular value for the conversion of cycloalkenes into fused 1,2,5-oxadiazole 2-oxides. 

[163] Mixtures of 1,2,5-oxadiazole 2(5)-oxide isomers may be formed for nonsymmetrical 

alkenes. The procedure (Table 6) involves initial reaction with dinitrogen trioxide to 

afford the 1-nitro-2-nitroso adduct 34, which is often isolated as the nitroso dimer 

(pseudonitrosite), followed by rearrangement to the Æ-nitro ketoxime tautomer 35, and 

finally dehydrative cyclization to the 1,2,5-oxadiazole 2-oxide 33 with sulfuric acid, phosphoric 

acid, chlorosulfonic acid, or sulfur trioxide–dimethylformamide complex. The 

method is not restricted to simple alkyl- and aryl-substituted 1,2,5-oxadiazole 2-oxides, 

and various functional groups can be accommodated; nitrosation of crotonaldehyde, for 

example, affords 4-methyl-1,2,5-oxadiazole-3-carbaldehyde 2-oxide (33, R 1 = Me; 

R 2 = CHO). [164] Alk-1-enes can lead directly to nitro-1,2,5-oxadiazole 2-oxides; for example 

3-methyl-4-nitro-1,2,5-oxadiazole 2-oxide (33, R 1 =NO 2;R 2 = Me) is formed from propene 

and dinitrogen trioxide. [165,166] Æ-Nitro ketoximes are also intermediates on a route to 

some D-glucose-fused 1,2,5-oxadiazole 2-oxides that involves the reaction of Æ-tosyloxy ketones 

with hydroxylamine in aqueous pyridine, followed by addition of nitrite to the resulting 

Æ-(hydroxyimino)pyridinium salt. [167] 


Table 6 1,2,5-Oxadiazole 2-Oxides by Dehydration of Æ-Nitro Ketoximes [161–166] 

R 1 

R 2 

N2O 3 



R 1 R 2 

ON NO2 

34 

R 1 R 2 

N NO 2 


Me Me PPA, 1108C, 15 min 88 [162] 

(CH2) 4 H2SO4, 1208C, 30 min 74 [162] 

(CH2) 6 H2SO4, 1258C, 15 min 80 [162] 

HO 

35 

ClSO 3H, DMF, rt, 30 min 72 [163] 

SO 3/DMF, rt, 30 min 62 [163] 

− H2O 

R 1 R 2 

N 

O 

33 

N + 

O − 

4,5,6,7-Tetrahydro-4,7-methano-2,1,3-benzoxadiazole 1-Oxide (33,R 1 ,R 2 = Cyclopentane- 

1,3-diyl); Typical Procedure: [163] 

A soln of chlorosulfonic acid (30 mL) in DMF (60 mL) was added to a soln of 3-nitronorbornan-2-one 

oxime (4.93 g, 28.9 mmol) in DMF (25 mL). After 30 min at rt, the mixture 

was poured into cold H 2O, and the pH was adjusted to ~10 by adding 10% aq NaOH. Extraction 

with CH 2Cl 2 (3 ” 50 mL) and evaporation of the solvent gave a solid that was recrystallized 

(toluene); yield: 3.17 g (72%); mp 708C. 



1,2,5-Oxadiazole 2-oxides bearing good leaving groups at the 3- and/or 4-positions readily 

undergo nucleophilic substitution reactions, similar to those for the corresponding 1,2,5oxadiazoles 

(see Section 13.7.1.3.1). [18] From a synthetic point of view, most attention has 

been paid to nitro-1,2,5-oxadiazole 2-oxides, [17] although displacement of halo and sulfonyl 

groups has also been reported. 

13.7.3.2.1.1 Method 1: 


Nucleophilic displacement reactions of halo-1,2,5-oxadiazole 2-oxides with amines may 

be accompanied by ring opening to form the corresponding glyoxime; however, under 

controlled conditions, the initial substitution product can sometimes be isolated. Treatment 

of 3,4-dibromo-1,2,5-oxadiazole 2-oxide with diethylamine at ambient temperature 

gives 1,2,5-oxadiazole-3,4-diamine 2-oxide in a good yield, whereas heating with ammonia 

or aniline affords the corresponding diaminoglyoximes. [168] Substitutions involving 

alkoxides and thiolates have proved to be more successful (Scheme 21); [169,170] for example, 

treatment of 3-chloro-4-methyl-1,2,5-oxadiazole 2-oxide (36, R 1 = Me; X = Cl) with potassium 

benzenethiolate gives the phenylsulfanyl compound 37 (R = Me; Nu = SPh). [169] 




Halo-1,2,5-oxadiazole 2-Oxides [169,170] 

R 1 X 

N 

O 

36 

N + 

O − 

X = Cl, Br; Nu = OR 2 , SR 2 

Nu − 

R 1 Nu 

N 

O 

37 

N + 

O − 

13.7.3.2.1.2 Method 2: 

Substitution of Sulfur by Nucleophiles 

An arenesulfonyl group attached to a 1,2,5-oxadiazole 2-oxide is readily displaced by alkoxides 

and thiolates. [101,160,171] Substitution can take place at both the 3- and 4-positions, 

although the 4-position is more reactive; for example, reaction of alkoxides with 3,4bis(arenesulfonyl)-1,2,5-oxadiazole 

2-oxides 38 affords the 4-alkoxy derivatives 39 in 

good yield (Scheme 22). Reaction with thiolates gives mixtures of 1,2,5-oxadiazole 2(5)-oxide 

isomers. [101,172] 


Sulfonyl-1,2,5-oxadiazole 2-Oxides [101,160,171] 

Ar 1 O 2S SO 2Ar 1 

N 

O 

38 

N + 

O − 

OR 1− 

R 1 O SO 2Ar 1 

N 

O 

13.7.3.2.1.3 Method 3: 

Substitution of Nitrogen by Nucleophiles 

39 

N + 

O − 

Nitrogen, oxygen, and sulfur nucleophiles readily displace the nitrite anion at the 4-position 

of the 1,2,5-oxadiazole 2-oxide ring. [17] For example, 3-methyl-4-nitro-1,2,5-oxadiazole 

2-oxide (40, R 1 = Me) reacts at room temperature with pyrrolidine, ethoxide, phenoxide, 

ethanethiolate, or benzenethiol to afford the substitution products 41 in yields of 53– 

85% (Scheme 23). [51] For 3-chloro-4-nitro-1,2,5-oxadiazole 2-oxide (40,R 1 = Cl), substitution 

occurs exclusively at the 4-position. [173] The experimental procedures employed are broadly 

similar to those for the corresponding nitro-1,2,5-oxadiazoles (see Section 13.7.1.3.1.3, 

Scheme 6). 


Nitro-1,2,5-oxadiazole 2-Oxides [17,51,173] 

O2N R 1 

N 

O 

40 

N + 

O − 

Nu = NR 2 2, OR 2 , OAr 1 , SR 2 , SAr 1 



Nu − 

Nu R 1 

N 

O 

41 

N + 

O − 

3-Methyl-4-phenoxy-1,2,5-oxadiazole 2-Oxide (41, Nu = OPh; R 1 = Me); Typical Procedure: [51] 

A soln of phenol (1.00 g, 10.7 mmol) and NaOH (0.48 g, 12 mmol) in a mixture of acetone 

(10 mL) and H 2O (3 mL) was added dropwise with stirring to a soln of 3-methyl-4-nitro- 


1,2,5-oxadiazole 2-oxide (40, R 1 = Me; 1.45 g, 10.0 mmol) in acetone (5 mL) at 15–258C. After 

a further 90 min at 208C, the solvent was partly removed under reduced pressure at rt. 

The residue was diluted with H 2O, and the resulting solid was collected by filtration, 

dried, and recrystallized (aq EtOH); yield: 1.15 g (60%); mp 120–1218C. 


The stability of the 1,2,5-oxadiazole 2-oxide ring allows functional-group transformations 

to be performed on substituents, particularly at the 4-position, in a manner similar to that 

described for monocyclic 1,2,5-oxadiazoles (see Section 13.7.1.3.2). The reactions of 1,2,5oxadiazolamine 

2-oxides and nitro-1,2,5-oxadiazole 2-oxides have been studied in detail, 

and their chemistries have been reviewed. [17] Although alkylation and arylation of 1,2,5oxadiazolamine 

2-oxides are unknown, these compounds can be readily acylated or sulfonated. 

1,2,5-Oxadiazolamine 2-oxides can also be oxidized to nitro-1,2,5-oxadiazole 2-oxides 

with peracids, [58,173] and to azo compounds with permanganate. [174] Nitro-1,2,5-oxadiazole 

2-oxides have been reduced to the corresponding amino compounds by using, for 

example, tin(II) chloride/hydrochloric acid or sodium dithionite. [175,176] Nitration of phenyl-1,2,5-oxadiazole 

2-oxides takes place mainly at the ortho and para positions, and it is 

noteworthy that both 3- and 4-phenyl-1,2,5-oxadiazole 2-oxide are nitrated on the phenyl 

substituent, leaving the oxadiazole ring intact. [177] A wide variety of transformations can 

be performed on carbon substituents, providing access to numerous derivatives. [18] For example, 

alkyl-1,2,5-oxadiazole 2-oxides can be halogenated to the haloalkyl compounds, 

which undergo nucleophilic substitution reactions with amines and alkoxides. 3- 

(Hydroxymethyl)-1,2,5-oxadiazole 2-oxides are oxidized to 1,2,5-oxadiazole-3-carbaldehyde 

2-oxides with manganese(IV) oxide, and to 1,2,5-oxadiazole-3-carboxylic acid 2-oxides 

by using Caro s acid. [178] Interconversion of 1,2,5-oxadiazolecarboxylic acid 2-oxides 

and their ester, acyl halide, nitrile, and amide derivatives have all been described. [50,179,180] 

Condensation of hydrazine with 3,4-diacyl-1,2,5-oxadiazole 2-oxides provides an efficient 

route to [1,2,5]oxadiazolo[3,4-d]pyridazine 1(3)-oxides [138] (see Section 13.7.4.1.2). 


2,1,3-Benzoxadiazole 1-Oxides (Benzofuroxans) and 

Other Annulated Furoxans 

The heterocyclic rings of 2,1,3-benzoxadiazole 1-oxides (benzofuroxans) have similar geometries 

to those of their monocyclic analogues, with short N1-O and long O2-N3 bonds; 

in the homocyclic ring, C4-C5 and C6-C7 are markedly shorter than C5-C6, implying a 

significant bond localization. [181] 2,1,3-Benzoxadiazole 1-oxide (4) is calculated to be less 

aromatic (I A = 81) than 2,1,3-benzoxadiazole (3; I A = 106). [21] The ring–chain tautomerism 

between 1-oxides and 3-oxides has been studied in considerable depth. [6,25,182] Isomerization 

occurs at ambient temperature and involves a 1,2-dinitrosoarene as an intermediate 

(Scheme 24). 

Scheme 24 Ring–Chain Tautomerism of 2,1,3-Benzoxadiazole 1-Oxide [6,25,182] 

O 

N 

O 

N 

− 

+ 


13.7.4 2,1,3-Benzoxadiazole 1-Oxides (Benzofuroxans)/Other Annulated Furoxans 207 

2,1,3-Benzoxadiazole 1-oxides are resistant to oxidation, but can readily be reduced to the 

corresponding 2-nitroanilines or benzene-1,2-diamines, depending on the reagent used. 

The parent 2,1,3-benzoxadiazole 1-oxide and all monosubstituted 2,1,3-benzoxadiazole 

NO 

NO 

N 

O 

N 

O − 

+ 



1-oxides are sensitive to bases, which cause ring cleavage to nitriles, nitrile oxides, and 

aci-nitro compounds (hydrocarbylideneazinic acids). Electrophilic and nucleophilic reactions 

generally take place in the homocyclic ring. From a synthetic point of view, the 

most significant reactions are those involving conversion of the oxadiazole oxide system 

into other heterocyclic systems, some of which show useful biological activity. Quinoxaline 

N-oxides are readily formed by treatment with enamines or enolate anions, [6,14,182,183] 

and benzimidazoles can be prepared by reaction with nitroalkanes. [6,14] Various 2,1,3benzoxadiazole 

1-oxides bearing unsaturated groups at the 4-position rearrange to form 

4(7)-nitro-substituted benzo-fused heterocycles. [84] For example, nitroindazoles are 

formed from imine, oxime, and hydrazone derivatives of 4-acyl-2,1,3-benzoxadiazole 1oxides, 

and 4-nitrobenzotriazoles can be prepared from 4-(arylazo)-2,1,3-benzoxadiazole 

1-oxides. The rearrangement reactions of 2,1,3-benzoxadiazole 1-oxides have been reviewed. 

[84] The N-oxide moiety in 2,1,3-benzoxadiazole 1-oxides activates the homocyclic 

ring to nucleophilic attack, so that 4-halo-7-nitro-2,1,3-benzoxadiazole 1-oxides react rapidly 

with phenols, thiols, and amines; the 5,7-dinitro analogues are even more reactive 

(see Section 13.7.4.3.1.2). 4,6-Dinitro-2,1,3-benzoxadiazole 1-oxide, [184] which is regarded 

as a superelectrophile, readily forms Meisenheimer complexes. 


13.7.4.1.1 By Annulation to an Arene 

13.7.4.1.1.1 By Formation of One O-N Bond 

13.7.4.1.1.1.1 Fragment O-N-C-C-N 

The principal methods for forming the heterocyclic ring of 2,1,3-benzoxadiazole 1-oxides 

involve the oxidation of benzo-1,2-quinone dioximes, the oxidation of 2-nitroanilines, 

and the thermolysis of 2-nitroaryl azides. [4] It should be noted that ring–chain tautomerism 

for the N-oxides (Scheme 24) of nonsymmetrically substituted 2,1,3-benzoxadiazole 1oxides 

occurs more readily than is the case for monocyclic analogues, and mixtures of isomers 

may result. [84] 

13.7.4.1.1.1.1.1 Method 1: 

From 1,2-Quinone Dioximes 

2,1,3-Benzoxadiazole 1-oxides 43 can readily be prepared by the oxidation of benzo-1,2quinone 

dioximes 42 (Scheme 25), a process similar to that used for the conversion of glyoximes 

into monocyclic 1,2,5-oxadiazole 2-oxides. Whereas the reaction is usually 

straightforward and high yielding, its utility is somewhat restricted by the limited availability 

of the starting materials, which are themselves often best prepared by reduction of 

the 2,1,3-benzoxadiazole 1-oxides. It is, however, a satisfactory approach when the parent 

quinone is accessible by other means, and it was by this route that the first aromatic furoxan, 

naphtho[1,2-c][1,2,5]oxadiazole 1(3)-oxide, was originally prepared. [194] Suitable oxidizing 

agents include hypohalites, ferricyanide, [194] nitric acid, and chlorine. [185] 

Scheme 25 2,1,3-Benzoxadiazole 1-Oxides by Oxidation of 1,2-Quinone Dioximes [185,194] 

R 1 

42 

OH 

N 

N 

OH 



Cl2, EtOH,

13.7.4.1.1.1.1.2 Method 2: 

From 2-Nitroanilines 

Oxidative ring closure of 2-nitroanilines is a widely used route to 2,1,3-benzoxadiazole 1oxides, 

with alkaline hypochlorite often being the reagent of choice (Table 7). [186] It is particularly 

useful when the azide decomposition route (see Section 13.7.4.1.1.1.1.3) is slow, 

but its scope is restricted by the instability of some 2,1,3-benzoxadiazole 1-oxides to alkaline 

oxidizing conditions. Phenyliodine(III) diacetate has also been used as the oxidant, [92] 

but this procedure is not always satisfactory, with azo compounds sometimes being 

formed as byproducts. [195] 

Table 7 2,1,3-Benzoxadiazole 1-Oxides by Oxidation of 2-Nitroanilines [94,186,187,190,197] 

R 2 

R 3 

R 1 

R 4 

NH 2 

NO 2 

[O] 

R 2 

R 3 

R 1 

R 4 

N 

O 

N 

O − 

+ 

R 1 R 2 R 3 R 4 Conditions Yield (%) Ref 

H H H H NaOCl, EtOH/KOH, 0 8C, 10 min 82 [186] 

H 1,2-C 6H 4 H PhI(OAc) 2, benzene, rt, 15 h 70 [197] 

H OMe H H NaOCl, EtOH/KOH, 0–58C 95 [94] 

H OCH 2CH 2O H NaOCl, EtOH/KOH, 0 8C 67 [190] 

2,1,3-Benzoxadiazole 1-Oxide; Typical Procedure: [186] 

Reprinted from (Mallory, Organic Syntheses, Collective Volume IV), Copyright (1963), 

p 74, with permission from John Wiley & Sons, Inc. 

A soln of NaOCl was prepared by the addition of Cl 2 (41 g) to aq NaOH (50 g in 300 mL), and 

added with stirring over 10 min to a soln of 2-nitroaniline (40 g, 290 mmol) in ethanolic 

KOH (21 g in 250 mL) at 08C. The resulting yellow precipitate was collected by filtration, 

washed with H 2O (200 mL), air-dried, and recrystallized (aq EtOH) to give a yellow solid; 

yield: 31.6–32.5 g (80–82%); mp 72–73 8C. 

13.7.4.1.1.1.1.3 Method 3: 

From 2-Nitroaryl Azides 



The thermal decompositon of 2-nitroaryl azides 44 is one of the most dependable routes 

to 2,1,3-benzoxadiazole 1-oxides and hetareno-fused analogues (Table 8). [187,196] On heating 

(e.g., in toluene or AcOH at 100–1208C), ring closure occurs with loss of dinitrogen. 

The relatively low temperatures required for these reactions, compared with those required 

for aryl azides in general, have been rationalized in terms of a concerted mechanism 

involving participation of the ortho-nitro group in the expulsion of dinitrogen from 

the azide. Numerous substituted 2,1,3-benzoxadiazole 1-oxides have been prepared by 

this method, which is also suitable for hetero-substituted analogues, including thieno, [197] 

imidazo, [198] oxadiazolo, [89,199] thiadiazolo, [199,200] pyrido, [201,202] pyrimidino, [203] and quinazolino 

[204] derivatives. A one-pot procedure has been developed for the conversion of 2-chloro-1-nitroarenes 

into 2,1,3-benzoxadiazole 1-oxides by treatment with sodium azide in 

the presence of a phase-transfer catalyst. [192] Photolysis of 2-nitroaryl azides can also yield 

2,1,3-benzoxadiazole 1-oxides. 



Table 8 2,1,3-Benzoxadiazole 1-Oxides from 2-Nitroaryl Azides [187–189,191–193,196] 

R 2 

R 3 

R 1 

R 4 

44 

N3 

NO 2 



heat 

− N2 

R 2 

R 3 

R 1 

R 4 

N 

O 

N 

O − 

+ 

R 1 R 2 R 3 R 4 Conditions Yield (%) Ref 

H H H H toluene, 1008C, 3 h 85 [187] 

H CHO H H toluene, 1008C, 30 min 82 [188] 

H OCMe2O H toluene, 1158C, 2 h 85 [189] 

H O(CH2) 3O H toluene, 1158C, 2 h 89 [191] 

H NO2HH ClCH2CH2Cl, BnNBu3Br, 608C, 6 h 95 [192] 

H NMe2 Cl H AcOH, reflux, 1 h 95 [193] 

2,1,3-Benzoxadiazole 1-Oxide; Typical Procedure: [187] 

Reprinted from (Smith, Boyer, Organic Syntheses, Collective Volume IV), Copyright 

(1963), p 75, with permission from John Wiley & Sons, Inc. 

A mixture of 2-nitrophenyl azide (16.4 g, 0.1 mol) and toluene (30 mL) was heated on a 

steam bath until gas evolution ceased (~3 h). On cooling, a straw-colored precipitate 

(~6 g) was formed, which was separated by filtration; a further ~5 g product was obtained 

by concentration of the mother liquor. Recrystallization (aq EtOH) gave a yellow solid; 

yield: 10.5–11.5 g (77–85%); mp 70–71 8C. 

2,1,3-Benzoxadiazole 1-Oxides; General Procedure: [192] 


The 2-chloro-1-nitrobenzene derivative (10 mmol) and powdered NaN 3 (650 mg, 10 mmol) 

were added to a vigorously stirred soln of Bu 3NBnBr (356 mg, 1 mmol) in 1,2-dichloroethane 

(50 mL). The mixture was heated to 608C over 15 min, and maintained at that temperature 

for a further 6 h. After cooling to 28 8C, the soln was filtered, the filtrate was washed 

sequentially with 1M aq HCl (100 mL) and H 2O (50 mL), and the organic layers were separated 

and dried (Na 2SO 4). Removal of the solvent under reduced pressure and recrystallization 

of the residue gave the title compound; yield: 42–97%. 

13.7.4.1.2 By Annulation to the Heterocyclic Ring 

2,1,3-Benzoxadiazole 1-oxides, like their 2,1,3-benzoxadiazole counterparts (see Section 

13.7.2.1.2), are not prepared by annulation to a preformed 1,2,5-oxadiazole ring. The reaction 

of appropriate substituents can, however, provide access to hetareno-fused analogues. 

For example, [1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxides 45 can be prepared by 

the condensation of hydrazine with 3,4-diacyl-1,2,5-oxadiazole 2-oxides (Scheme 26). [112] 


Scheme 26 [1,2,5]Oxadiazolopyridazine 1-Oxides from 

3,4-Diacyl-1,2,5-oxadiazole 2-Oxides [112] 

Ar 1 

O 

N 

O 

O 

Ar 1 

N + 

O − 

H2NNH2 

Ar 1 

N 

N 

N 

O 

N 

O 

45 

− 

+ 

Ar1 4,7-Bis(3-nitrophenyl)-[1,2,5]oxadiazolo[3,4-d]pyridazine 1-Oxide (45, Ar 1 = 3-O 2NC 6H 4); 


A soln of H 2NNH 2 •HCl (7 g, 0.1 mol) in hot MeOH (100 mL) was added to a soln of 3,4-bis(3nitrobenzoyl)-1,2,5-oxadiazole 

2-oxide (21 g, 0.55 mol), and the mixture was refluxed for 

1 h. The precipitated solid was separated by filtration, washed with H 2O, dried in air, 

and treated with hot benzene (CAUTION: carcinogen) to remove unreacted starting material. 

The product was recrystallized (2-nitropropane); yield: 18.0 g (86%); mp 2518C. 

13.7.4.2 Synthesis by Ring Transformation 

Various 4-nitro-2,1,3-benzoxadiazole 1-oxides undergo the Boulton–Katritzky rearrangement 

(Scheme 27). [25,27] For example, heating 5-chloro-4-nitro-2,1,3-benzoxadiazole 1-oxide 

(46, R 1 =H;R 2 = Cl) affords the 7-chloro isomer 47 (R 1 =H;R 2 = Cl), [205] and nitration of 

5-methyl-2,1,3-benzoxadiazole 1-oxide yields 7-methyl-4-nitro-2,1,3-benzoxadiazole 1-oxide 

(47, R 1 =H;R 2 = Me) via the 5-methyl-4-nitro isomer 46 (R 1 =H;R 2 = Me). [205,206] Similar 

rearrangements also occur for 5,6-(alkylenedioxy)-4-nitro-2,1,3-benzoxadiazole 1-oxides 

(i.e., 46 fi 47, where R 1 ,R 2 = O(CH 2) nO; n = 3–5). [189,207,208] Similarly, 6-chloro-7-nitrobenzisoxazole 

on warming yields 7-chloro-2,1,3-benzoxadiazole-4-carbaldehyde 1-oxide. [209] 

Scheme 27 Rearrangement of 4-Nitro-2,1,3-benzoxadiazole 1-Oxides [205] 

R 1 

R 2 

NO 2 

46 

O 

N 

O 

N 

− 

+ 


heat 


13.7.4.3.1.1 Method 1: 

Substitution of Hydrogen 



R 1 

Electrophilic substitution occurs preferentially at the 4- and 6-positions. Nitration of 

2,1,3-benzoxadiazole 1-oxide occurs initially at the 4-position, and under more-forcing 

conditions the 4,6-dinitro compound is formed. [210,211] 5-Substituted analogues react similarly. 

Nitration of 5-chloro-2,1,3-benzoxadiazole 1-oxide (48)at08C affords the 5-chloro-4nitro 

compound 49, which on heating rearranges to 7-chloro-4-nitro-2,1,3-benzoxadiazole 

1-oxide (50); under more-forcing conditions of nitration, compound 48 yields 5chloro-4,6-dinitro-2,1,3-benzoxadiazole 

1-oxide (51), which rearranges to the 7-chloro- 

4,6-dinitro isomer 52 (Scheme 28). [89,212] 

NO2 

R 2 

47 

N 

O 

N 

O − 

+ 



Scheme 28 Nitration of 5-Chloro-2,1,3-benzoxadiazole 1-Oxide [89,212] 

Cl 

Cl 

48 

48 

O 

N 

O 

N 

− 

O 

N 

O 

N 

Cl 

− 

H2SO4, HNO3 

0 o + 

C 

90% 

+ 

AcOH 

heat 

72% 

O 

N 

O 

N 

− 

+ 



H 2SO 4, HNO 3 

21 o C 

NO 2 

49 

NO 2 

Cl 

50 

N 

O 

N 

O − 

+ 

O 

N 

O 

N 

− 

O2N N 

O 

NO2 

N 

O 

51 

− 

NO2 

+ 

Cl 

O2N Cl 

+ 

52 

5-Chloro-4-nitro-2,1,3-benzoxadiazole 1-Oxide (49) and 7-Chloro-4-nitro-2,1,3-benzoxadiazole 

1-Oxide (50); Typical Procedure: [89] 

A soln of 5-chloro-2,1,3-benzoxadiazole 1-oxide (10.0 g, 58.7 mmol) in H 2SO 4 (60 mL) was 

treated at 08C with a mixture of HNO 3 (d = 1.5; 4.03 g) and H 2SO 4 (10 mL). After 15 min, 

the mixture was poured into ice water to afford title compound 49, which was recrystallized 

(CH 2Cl 2/CCl 4); yield: 11.4 g (90%); mp 68–70 8C. 

A soln of compound 49 (2.0 g) in AcOH was refluxed for 30 min, diluted with H 2O, and 

the resulting precipitate was crystallized (AcOH) to give orange prisms of 50; yield: 1.45 g 

(72%); mp 137–1388C. 

4,6-Dinitro-2,1,3-benzoxadiazole 1-Oxide (47,R 1 =NO 2;R 2 = H); Typical Procedure: [210,211] 

CAUTION: 4,6-Dinitro-2,1,3-benzoxadiazole 1-oxide is a powerful explosive with an activity 

comparable to that of dry picric acid. [210] 

A cooled mixture of HNO 3 (d = 1.52; 15 mL) and concd H 2SO 4 (40 mL) was added dropwise 

to a stirred soln of 2,1,3-benzoxadiazole 1-oxide (10.0 g, 73.5 mmol) in concd H 2SO 4 

(120 mL) at 08C at such a rate that the temperature did not exceed 5 8C. After 30 min at 

08C, the mixture was warmed to 408C and then poured onto crushed ice. The resulting 

precipitate was separated by filtration, washed with H 2O, air-dried, and recrystallized 

(EtOAc) to give yellow needles; yield: 9.14 g (55%); mp 173–174.58C. 

13.7.4.3.1.2 Method 2: 


The nucleophilic substitution reactions of 2,1,3-benzoxadiazole 1-oxides are similar to 

those of 2,1,3-benzoxadiazoles (see Section 13.7.2.3.1.2), but with additional reactivity 

being conferred by the presence of the N-oxide moiety. Halides are displaced by various 

nucleophiles, including alkoxides, phenoxides, thiolates, and amines. Their reactivity is 

further enhanced by the presence of nitro groups. For example, 7-halo-4-nitro-2,1,3-benzoxadiazole 

1-oxides react rapidly with amines, thiols, and phenoxides to afford the 7-substituted 

4-nitro derivatives (Scheme 29). [188,213–215] Treatment of chloronitro-2,1,3-benzoxadiazole 

1-oxides with sodium azide provides a convenient route to benzo[1,2-c:3,4-c¢]bis[1,2,5]oxadiazole 

1,6-dioxide (54, Scheme 30). [89] 7-Chloro-4-nitro-2,1,3-benzoxadiazole 

1-oxide (50) reacts with sodium azide to give the expected azido derivative 53, thermolysis 

of which affords benzo[1,2-c:3,4-c¢]bis[1,2,5]oxadiazole 1,6-dioxide (54); the 5-chloro-4nitro 

compound 49 reacts with sodium azide to yield 54 directly without isolation of the 

intermediate azide. Benzo[1,2-c:3,4-c¢:5,6-c¢¢]tris[1,2,5]oxadiazole 1,4,7-trioxide (55) can be 


prepared similarly by treatment of 1,3,5-trichloro-2,4-dinitrobenzene with sodium azide, 

nitration of the trisazide, and thermolysis of the resulting 1,3,5-triazido-2,4,6-trinitrobenzene. 

[216,217] 7-Chloro-4,6-dinitro-2,1,3-benzoxadiazole 1-oxide (52) is even more reactive 

toward nucleophiles. [218] It reacts with primary and secondary arylamines to afford a mixture 

of 5- and 7-(arylamino)-4,6-dinitro-2,1,3-benzoxadiazole 1-oxides, and even N,N-dimethylaniline 

is a sufficiently reactive carbon nucleophile to displace the chloride to 

form 5- and 7-[4-(dimethylamino)phenyl]-4,6-dinitro-2,1,3-benzoxadiazole 1-oxide. 


7-Halo-4-nitro-2,1,3-benzoxadiazole 1-Oxides [188,213–215] 

N 

O 

N 

O − 

NO2 N 

O 

N 

O − 

Nu − 

NO2 + + 

X Nu 

X = F, Cl; Nu = OAr 1 , SR 1 , NR 1 2, N3 

Scheme 30 Synthesis of Benzo[1,2-c:3,4-c¢]bis[1,2,5]oxadiazole 1,6-Dioxide [89,216,217] 

Cl 

N 

O 

N 

O − 

NO2 N 

O 

N 

O − 

NO2 

NaN3 − Cl 

Cl N3 − 

+ + 

50 

O 

N 

NO2 

− 

O 

+ 

N 

O N 

49 

O 

N 

− 

+ 

55 

N 

O 

N 

O − 

+ 

N 

O 

N 

O − 

+ 



NaN3 

− Cl − 

− N2 

53 

− 

O 

+ N 

O 

N 

54 

− N 2 

+ N O 

N 

− 

O 

− 

O 

+ N 

O 

N 

7-Azido-4-nitro-2,1,3-benzoxadiazole 1-Oxide (53); Typical Procedure: [89] 


54 

+ N O 

N 

− 

O 

A soln of NaN 3 (0.15 g, 2.7 mmol) in acetone/MeOH/H 2O (1:2:2; 1 mL) was added to a soln of 

7-chloro-4-nitro-2,1,3-benzoxadiazole 1-oxide (50; 0.5 g, 2.3 mmol) in acetone/MeOH (1:1; 

1 mL). After 1 h at 208C, the mixture was diluted with H 2O, and the precipitated solids 

were separated by filtration and recrystallized (EtOH) to give dark red crystals; yield: 

0.4 g (80%); mp 118–1198C (dec with decrepitation at 838C). 



Benzo[1,2-c:3,4-c¢]bis[1,2,5]oxadiazole 1,6-Dioxide (54): [89] 


A soln of NaN 3 (3.36 g, 51.6 mmol) in acetone/MeOH/H 2O (1:2:2; 25 mL) was added to a soln 

of 5-chloro-4-nitro-2,1,3-benzoxadiazole 1-oxide (49; 11.1 g, 51.5 mmol) in acetone/MeOH 

(1:1; 25 mL). When the spontaneous effervescence had ceased (1 h), H 2O was added and 

the resulting precipitate was separated by filtration. Recrystallization (EtOH) gave pale 

yellow crystals; yield: 5.1 g (51%); mp 94–95 8C. 

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