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

Abstract

Achieving 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.