Palladium(0)‐Catalyzed Enantioselective Intramolecular Arylation of Enantiotopic Secondary C−H Bonds

Abstract

The enantioselective functionalization of nonactivated enantiotopic secondary C−H bonds is one of the greatest challenges in transition‐metal‐catalyzed C−H activation proceeding by an inner‐sphere mechanism. Such reactions have remained elusive within the realm of Pd0 catalysis. Reported here is the unique reactivity profile of the IBiox ligand family in the Pd0‐catalyzed intramolecular arylation of such nonactivated secondary C−H bonds. Chiral C2‐symmetric IBiox ligands led to high enantioselectivities for a broad range of valuable indane products containing a tertiary stereocenter, as well as the arylation of secondary C−H bonds adjacent to amides. Depending on the amide substituents and upon control of reaction time, indanes containing labile tertiary stereocenters were also obtained with high enantioselectivities. Analysis of the steric maps of the IBiox ligands indicated that the level of enantioselectivity correlates with the difference between the two most occupied and the two less occupied space quadrants, and provided a blueprint for the design of even more efficient ligands.

Remote Construction of N‐Heterocycles via 1,4‐Palladium Shift‐Mediated Double C−H Activation

“…[Pd(π‐allyl)Cl] 2 /NHC (NHC=N‐heterocyclic carbene), [16] Pd 2 dba 3 /PR 3 [4, 9] and Pd(PPh 3 ) 4 [10] (Table 1, entries 1–5, see Table S1 for details). As a result, IBioxMe 4 [16b, 17] was identified as the optimal ligand to convert substrate 7 a to the desired indoline 8 a in 99 % NMR yield, and minimize the formation of the direct C(sp 2 )−H arylation product 9 a , N‐demethylated product 10 a , and proto‐dehalogenated product 11 a (entry 1). Interestingly, the previously developed conditions for 1,4‐Pd shift‐mediated double C−H activation reactions employing phosphine ligands provided 9 a as the major product (entries 3–5).…”