[Multi-component Reactions Based on Formal [2+2] Reaction of Benzyne with Formamide]

Arynes, such as benzyne, are highly strained and kinetically unstable intermediates that have been widely employed in organic synthesis. In particular, since the initial report regarding the in situ generation of arynes under neutral conditions from ortho-(trimethylsilyl)aryl triflates and fluoride ions in 1983, numerous nucleophilic additions to arynes have been utilized in the synthesis of carbocycles, heterocycles, and multi-substituted arenes. Recently, we reported the insertion of arynes into the π-bond in formamides, as well as related cascade reactions. First, we synthesized salicylaldehydes and aminophenols via the insertion of arynes into the C=O bond of sterically less hindered N,N-dimethylformamide (DMF). Notably, computational studies revealed the generation of unstable benzoxetene and ortho-quinone methide as reactive intermediates. We also studied multi-component coupling reactions leading to 2H-chromenes, coumarins, and xanthen-1-ones under mild conditions through the stepwise release of the strain energy in arynes. Furthermore, we studied the synthesis of O-heterocycles such as dihydrobenzofuran, benzofuran, and 4H-chromene as an application of our method. In this review, we will describe these studies in detail.