5-Chloromethyl-l,2,4-oxadiazole

The 3- and 5-chloromethyl-l,2,4-oxadiazoles 158 and 159 react with the pyrazolyl purine shown in Scheme 20 to give the corresponding (l,2,4-oxadiazol-5-yl)- and (l,2,4-oxadiazol-3-yl)methyl derivatives 160 and 161, respectively <2006BML302>. 

The polymer-supported 5-chloromethyl-l,2,4-oxadiazole 162 undergoes easy reaction with primary amines to give the 5-aminomethyl oxadiazoles 163, which serve as excellent substrates for the synthesis of amides or sulfonamides 164 (Scheme 21 - yields not reported) <1999TL8547>. 

However, with liquid ammonia or anhydrous methylamine 1,2,4-oxadiazines (88) are formed. 5-(Chloromethyl)-l,2,4-oxadiazoles (e.g., (86) react with urotropin to form salts, which are hydrolyzed with hydrochloric acid to 5-(aminomethyl) compounds (the Delepine reaction). Alternatively, 5-(aminomethyl)-l,2,4-oxadiazoles have been prepared by condensation of amidoximes with a-amino-acids <72JHC435>. 

From 3- or 5-chloromethyl-l,2,4-oxadiazoles, the 3- or 5-carbaldehydes, respectively, have been prepared by the Krohnke reaction <79JHC1469>. These aldehydes exist predominantely as hydrates (164) and (165), which are stabilized by intramolecular hydrogen bonds. 

In the context of preparing potential inhibitors of histone deacetylase, Vasudevan and a team from Abbott have described the cyclization of 1,2-diacylhydrazides to 1,3,4-oxadiazoles with Burgess reagent under microwave conditions (150 °C, 15 min) (Scheme 6.224 a) [232], A different approach was chosen by Natero and coworkers, who prepared 2-chloromethyl-l,3,4-oxadiazoles by treatment of acyl hydrazides with 1-chloro-2,2,2-trimethoxyethane (Scheme 6.224b) [401]. Here, the reagent was used as solvent and the mixture was heated by microwave irradiation at 160 °C for 5 min. 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

The reaction of 5-aryl-3-(chloromethyl)[l,3,4]oxadiazole-2(3//)-thiones 100 with hydrazine or methylhydrazine yields the corresponding 2,3-dihydro[l,2,4]triazolo[3,4-A][l,3,4]oxadiazole derivatives 102 <1984JCED477>. By analogy, hydrazine and phenylhydrazine convert the [l,2,4]triazole-2(3//)-thiones 101 into 3,7-dihydro-2//-[l,2,4 tria-zolo[4,3-r][ 1,2,4] triazoles 103 <1992PS99, 2002JCCS1035>. Finally, the azole-2(3//)-thiones 101 react with hydroxylamine to form the 3,7-dihydro[l,2,4]triazolo[5,l-d[l,2,4]oxadiazoles 104 (Scheme 8) <1992PS99>. 

Acylation with the chloroacetyl chloride in o-xylene. 5-Aryl- and 5-heteryltetrazoles react with chloroacetyl chloride in o-xylene (30—10 ( ) to form 5-aryl-2-chloromethyl-l,3,4-oxadiazoles, 2-chloromethyl-5-(l,5-dimethyl-2-pyrrolyl)-1,3,4-oxadiazole, and 2-chloromethyl-5-(5-methyl-2-furyl)-l,3,4-oxadiazole in 80-93% yields (cf. Section 6.07.5.2.2, Equation 16) <2005RJA773>. 

Natero et al. [31] gave the one-step synthesis of 5-phenyl-2-chloromethyl-l,3,4-oxadiazoles (xxviii) from commercially available acylhydrazides (xxvii) using l-chloro-2,2,2-trimethoxyethane (xxvi) as a solvent under microwave conditions. 

The reaction of 5-aryl-3-(chloromethyl)[l,3,4]oxadiazole-2(3//)-thiones (129) with hydrazine or methylhydrazine yields the corresponding 2,3-dihydro[l,2,4]triazolo[3,4-Z>][l,3,4]oxadiazole derivatives 30) (Equation (34)) <84JCED477>. 

The reaction of 3,5-dimethyl-l-thia-3,5-diazacyclohexane 41c with 1 or 2equiv of BHa-THF initially gives the monoadduct 63, which further disproportionates to the bis-adduct 45 as shown by their NMR spectra. In both adducts, the N-BH3 groups are in the equatorial positions, as indicated by the NMR chemical shifts of the N-CH3 groups <1999EJ12069>. The nitroimino[l,3,5]oxadiazinane 119 reacts with 2-chloromethyl-5-aryl-l,3,4-oxadiazoles 120 in DMSO in the presence of NaH to give oxadiazine derivatives 121 in 26-43% yield (Equation 21) <2002HC0601>. 

It has been demonstrated that 2,5-bis-(chloromethyl)-l,3,4-oxadiazole can undergo anionic polymerization. With sodium alcoholate, poly(l,3,4-oxa-diazole-2,5-diyl-l,2-vinylene) is formed, however the reaction cannot be controlled even at temperatures as low as —40°C. Instead, the exothermic reaction can be controlled by performing the polymerization at a toluene/ water interface with tetrabutylphosphonium bromide as a phase transfer catalyst. The mechanism is shown in Figure 10.7. 

Bis-(chloromethyl)-l,3,4-oxadiazole, 337, 338 Bis-(4-chlorophenyl)-sulfone, 241, 242, 291 Bis-(2,4-di-fert-butylphenyl)-pentaerythritol diphosphite, 363... 

It has been demonstrated that 2,5-bis-(chloromethyl)-l,3,4-oxadiazole can undergo anionic... 

MercaptomethyM-phcnyl-l,2,5-oxadiazol iV-2-oxide 102 and 3-(4-mercaptophenylmethylidenhydrazinocarbo-nyloxymethyl)-4-phenyl-l,2,5-oxadiazol iV-2-oxide 104 were successfully synthesized from 3-chloromethyl- or 3-hydroxymethyl-4-phenyl-l,2,5-oxadiazole iV-2-oxide 103 (Scheme 27) <2006AP59>. 

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