Abstract
AbstractThe palladium‐catalysed sp3 C−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 C−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 C−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 C−H arylation could be improved significantly using 3‐methylpicolinamide as the directing group and/or 3‐methylpentan‐3‐ol as the solventmagnified image
Highlights
Palladium-mediated CÀ H functionalisation reactions provide a powerful approach for selective transformation of individual CÀ H bonds on sp3 -rich scaffolds.[1]
The unsubstituted picolinamide 1 a gives an excellent yield of monoarylated product 2 a under our optimised reaction conditions, with no trace of methyl CÀ H activation
The 3-trifluoromethylpicolinamide 1 e provided the largest quantity of diarylated product 3 e as well as giving a high overall product yield
Summary
Palladium-mediated CÀ H functionalisation reactions provide a powerful approach for selective transformation of individual CÀ H bonds on sp3 -rich scaffolds.[1] Given the increasing importance of these compounds in medicinal chemistry,[2] the ability to selectively introduce novel functionality at particular locations in the molecular framework could provide a highly useful tool in drug development. Nitrogen-rich scaffolds are of particular importance in a wide range of chemistry-related fields, so nitrogen-linked directing groups have been the focus of considerable attention.[5] In 2005 Daugulis introduced the 8-aminoquinoline and picolinamide directing groups,[5a] and since a number of nitrogen-linked directing groups for CÀ H activation have been reported (Figure 1).[5] Typically, these directing groups deliver the palladium catalyst to a nearby CÀ H bond via the formation of a 5- or 6membered palladacycle, though transannular functionalisation reactions have been observed in some cases.[5d]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callSimilar Papers
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
