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

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(sp(3))-H arylation, C(sp(2))-H arylation, reductive Heck reaction, and domino Heck reaction/alkylation of aryl C(sp(2))-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(sp(3))-H arylation of the substrates providing dihydropyrazolo[1,5-b]isoquinolin-2(1H)-ones at 100 degrees C, and isomerization of the dihydropyrazolo[1,5-b]isoquinolin-2(1H)-ones gave isoquinoline derivatives at a higher temperature (140 degrees C); (ii) Sodium acetate (NaOAc) mediated the aryl C(sp(2))-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(sp(2))-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.

Automated summary

Achieving site-selectivity and chemoselectivity is challenging for substrates with multi-reactive sites in organic reactions. In this study, four different reactions were explored using model substrates with six reactive sites. By varying the reaction conditions, different bases were found to control the site-selectivity and chemoselectivity of the reactions. This strategy of "one substrate - multiple reactions - multiple products" reduces cost, increases product diversity, and provides more opportunities for pharmaceutical screening.