Tuning Reactivity in Pd‐catalysed C(sp³)‐H Arylations via Directing Group Modifications and Solvent Selection

Abstract

The palladium-catalysed sp 3 CÀ H arylation of a selection of saturated amine scaffolds was investigated using substituted picolinamide directing groups. On the bornylamine scaffold, highly selective monoarylation takes place using unsubstituted picolinamide or 3-methylpicolinamide, whereas a double CÀ H arylation occurs with other substituents present, becoming a significant product with 3-trifluoromethylpicolinamide. DFT calculations were used to help rationalise the effect of directing groups on the CÀ H palladation steps which were found experimentally to be irreversible. The substituted picolinamide directing groups were also examined on acyclic amine scaffolds and in many cases increased yields and selectivity could be obtained using methylpicolinamides. For a selection of other amine scaffolds, the yield of CÀ H arylation could be improved significantly using 3-methylpicolinamide as the directing group and/or 3methylpentan-3-ol as the solvent

Remote C–H Amination and Alkylation of Camphor at C8 through Hydrogen-Atom Abstraction

“…9 In addition, Sheppard and co-workers achieved effective C6 arylations using amine-based directing groups (see D). 10 Recently, the Costas group demonstrated that the carboxylic acid group of ketopinic acid could be used to achieve a manganese-catalyzed C8 lactonization (see E). 11 Although a variety of methods that functionalize the C−H group at C10 have been achieved, C−H functionalization at C8 remains elusive, particularly using the carbonyl group that is intrinsic to camphor.…”

“…While these methods take advantage of the ketone group resident in camphor ( 4 ), borneol and isoborneol derivatives (i.e., the hydroxy group) have also been shown to be effective directing groups for C10 functionalization (see B and C ) . In addition, Sheppard and co-workers achieved effective C6 arylations using amine-based directing groups (see D ) . Recently, the Costas group demonstrated that the carboxylic acid group of ketopinic acid could be used to achieve a manganese-catalyzed C8 lactonization (see E ) …”