Bronsted Base Prompted sp 3 C-H Latent Nucleophiles to Access α-Branched Amines Bearing β-Carbonyl by Cleaving Amide and Ester Bonds

alpha-Branched amines are key motifs that exist ina plethoraof natural products and pharmaceuticals. Herein we disclose the firstconvergent synthesis of alpha-branched amines bearing beta-carbonylin isoindolinones by employing unactivated tertiaryamides and unactivated alkyl esters as benign electrophilesources. The reaction proceeds by the direct aroylation of a C(sp (3))-H carbon adjacent to the nitrogenatom in core isoindolinones. Several amides and esters were screenedto choose the potential acyl source for the substrate scope. The reactionis carried out with a repertoire of substrates under mild conditionsand shows high functional group compatibility. Remarkably the reactionis amenable to organometallic ferrocenyl ester and indole methyl estersbearing an acidic NH moiety. Strikingly no trace of amidation product 8 is observed. In particular alpha-branched amines bearing beta-carbonyl synthesized from indole methyl esters are consideredimportant targets, as both motifs are prevalent in many drugs. Thisprotocol is scalable, and products obtained from indole methyl estersshow strong solid-state emission properties which are complementarywith DFT calculations.

Automated summary

alpha-Branched amines bearing beta-carbonyl in isoindolinones were synthesized via the aroylation of C(sp (3))-H carbon adjacent to the nitrogen atom. Unactivated tertiary amides and unactivated alkyl esters were used as electrophile sources. The reaction showed high functional group compatibility and could be applied to a range of substrates, including organometallic ferrocenyl esters and indole methyl esters with an acidic NH moiety.