Of 1,3,4-oxadiazoles

In contrast to pyridine chemistry, the range of nucleophilic alkylations that can be effected on neutral azoles is quite limited. Lithium reagents can add at the 5-position of 1,2,4-oxadiazoles (Scheme 16) (70CJC2006). Benzazoles are attacked by organometallic compounds at the C=N a-position unless it is blocked. 

Oxygen-containing azoles are readily reduced, usually with ring scission. Only acyclic products have been reported from the reductions with complex metal hydrides of oxazoles (e.g. 209 210), isoxazoles (e.g. 211 212), benzoxazoles (e.g. 213 214) and benzoxazolinones (e.g. 215, 216->214). Reductions of 1,2,4-oxadiazoles always involve ring scission. Lithium aluminum hydride breaks the C—O bond in the ring Scheme 19) 76AHC(20)65>. 

Catalytic reduction of 1,2,4-oxadiazoles also breaks the N—O bond e.g. (264) gives (265). Benzofuroxan can be reduced under various conditions to benzofurazan (266), the dioxime (267) or o-phenylenediamine (268) (69AHC(10)l). Reduction by copper and hydrochloric acid produced o-nitroanilines (Scheme 30) (69AHC(lO)l). 

Scheme 12 Synthesis of 1,2,4-oxadiazoles from carboxylic acids and amidoximes using PS-reagents...

Table 43 Photochemical rearrangement of 1,2,4-oxadiazoles to give substituted 1,2,4-triazole derivatives (Equation 63)...

Irradiation of 1,2,4-oxadiazoles 205 bearing fluorinated substituents in the 3- or 5-positions in the presence of an amine delivered the corresponding 1,2,4-triazoles 206a-e and 207a-e via a photochemical rearrangement. Several other competing reactions served to divert some of the reactive intermediates and, hence, yields of the fluorinated triazoles were modest (Equation 64 and Table 44) <2005H(65)387>. 

Ring syntheses of 1,2,4-oxadiazoles from a one-atom component and a four-atom component 272... 

As reported in CHEC-II(1996) <1996CHEC-II(4)179> and in more recent reviews <2001JCM209, 2004HOU(13)127>, the 3-position is remarkably stable to attack by nucleophiles and there are no additions to this aspect of the chemistry of 1,2,4-oxadiazoles since the appearance of CHEC-II(1996). 

The Mukaiyama-Hoshino reaction between a nitroalkane and phenyl isocyanate generates a nitrile oxide, and this method has been used in the synthesis of 1,2,4-oxadiazoles as discussed in CHEC-II(1996) <1996CHEC-II(4)179>. In a more recent advance, nitroethane undergoes ultrasound-mediated cycloaddition with trichloroacetonitrile to give the extremely useful (see Equation 11) 5-trichloromethyl-l,2,4-oxadiazole 228 (Equation 45) <1995TL4471>. 

In a significant addition to the synthesis of 1,2,4-oxadiazoles (Scheme 41), Itoh et al. discovered that the treatment of nitriles with iron(lll) nitrate in the presence of acetone or acetophenone gives the 3-acetyl- or 3-benzoyl-l,2,4-oxadiazoles 260, proposing that enolization and nitration gives an a-nitroketone, which then undergoes an acid-catalyzed dehydration to give the nitrile oxides 259 <2005S1935>. 

The use of polymer-supported reagents in combinatorial chemistry has received much attention in recent years, and a polymer-supported acylating reagent (supported on a ROMPGEL) has been used for the synthesis of 1,2,4-oxadiazoles in solution, (see Equation 37), <2000CCHT131>. 

Furoxan and furazans alcohols are relatively uncommon compounds, but they can serve as useful precursors to various new derivatives of 1,2,4-oxadiazole. 3-Hydroxy-4-nitrofurazan 208 reacts with iodosylbenzene to produce a highly reactive intermediate phenyliodonium nitrofurazanylate 209 which can be converted to a series of alkynyl(phenyl)-iodonium nitrofurazanylates and related products (Scheme 48) <2001TL5759>. 

Amino derivatives of 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles interact with phenyl isocyanate to produce various 3-substituted 5-amino-l,2,4-thiadiazoles, via intermediate thioureides which can be isolated. The tendency to rearrange follows the order 1,2,4-oxadiazoles, isoxazoles, and 1,2,5-oxadiazoles <1996CHEC-II(4)307>. 

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