Base‐Controlled Palladium‐Catalyzed Intramolecular ‘One Substrate ‐ Five Reactions’ of 5‐Benzyl‐1‐(2‐halobenzyl)‐2‐phenyl‐1H‐pyrazol‐3(2H)‐ones

Abstract

AbstractAchieving site‐selectivity and chemoselectivity is enormously challenging for substrates with multi‐reactive sites in organic reactions. One kind of model substrates, 5‐benzyl‐1‐(2‐halobenzyl)‐2‐phenyl‐1H‐pyrazol‐3(2H)‐ones with six reactive sites were chosen as the examples to probe their intramolecular four kinds of five reactions including C(sp3)−H arylation, C(sp2)−H arylation, reductive Heck reaction, and domino Heck reaction/alkylation of aryl C(sp2)−H bonds through variation of the reaction conditions. Screening of the reaction conditions showed that the different bases controlled the palladium‐catalyzed intramolecular site‐selectivity and chemoselectivity of the substrates: (i) Cesium carbonate (Cs2CO3) promoted the benzyl C(sp3)−H arylation of the substrates providing dihydropyrazolo[1,5‐b]isoquinolin‐2(1H)‐ones at 100 °C, and isomerization of the dihydropyrazolo[1,5‐b]isoquinolin‐2(1H)‐ones gave isoquinoline derivatives at a higher temperature (140 °C); (ii) Sodium acetate (NaOAc) mediated the aryl C(sp2)−H arylation of the substrates affording seven‐membered biphenyl N‐heterocycles; (iii) Sodium dichloroacetate (Cl2HCCO2Na) facilitated occurrence of the reductive Heck reaction of the substrates affording 1H‐pyrazolo[5,1‐a]isoindol‐2(8H)‐ones; (iv) Sodium trifluoroacetate (F3CCO2Na) assisted performance of the domino Heck reaction/aryl C(sp2)−H alkylation of the substrates leading to the spiro heterocycles. The ‘one substrate ‐ multiple reactions ‐ multiple products’ strategy greatly reduces cost, increases diversity of products, provides more opportunity for screening of pharmaceutical molecules, and enriches modern organic synthetic chemistry.