Microwave irradiation, aryl cycloaddition reaction

Azizian et al. [103] described a novel four-component reaction for the diastereo-selective synthesis of spiro-pyrrolizidines 170 using a 1,3-dipolar cycloaddition of azomethine ylides to N-aryl maleimides. Reaction of ninhydrin 166 with 1,2-phenylenediamine 167 in DMSO, and addition of L-proline 168 and N-aryl maleimides 169 in a one-pot four-component reaction (Scheme 11.41) usually required extended reaction times of up to 3 h at 100 °C to obtain the desired spiro-pyrrolizidines 170 in 76-86% yield as single diastereoisomers. This process can be accelerated substantially (3-5 min) with good yields (87-95%) by performing the reaction under microwave irradiation conditions. 

Another interesting type of 1,3-dipolar cycloaddition with azides involves condensation with nitriles as dipolarophiles to form tetrazoles. These products are of particular interest to the medicinal chemist, because they probably constitute the most commonly used bioisostere of the carboxyl group. Reaction times of many hours are typically required for the palladium-catalyzed cyanation of aryl bromides under the action of conventional heating. The subsequent conversion of nitriles to tetrazoles requires even longer reaction times of up to 10 days to achieve completion. Under microwave irradiation conditions, however, the nitriles are rapidly and smoothly converted to tetrazoles in high yields. An example of a one-pot reaction is shown in Scheme 11.54 [110], in which the second step, i.e. the cycloaddition, was achieved successfully under the action of careful microwave irradiation. The flash heating method is also suitable for conversion of 212 and 214 to tetrazoles 213 and 215, respectively, on a solid support, as shown in Scheme 11.54. 

Shie and Fang (2003) carried out oxidation of some aromatic aldehydes with in ammonia water and in situ cycloadditions with NaNj/ZnBr under microwave irradiation at 80 °C for 10 min to afford 5-aryl-l,2,3,4-tetrazoles in 70-83% yields. This microwave-accelerated reaction in aqueous media is quite safer and more efficient than conventional heating using prolonged reflux (17-48 h) at a high temperature (>100 °C)... 

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