title: Palladium-catalysed transannular C-H functionalization of alicyclic amines.
abstract: Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C-H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C-H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C-H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C-H bonds to C-C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, Michigan 48109, United States.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Topczewski
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, Michigan 48109, United States.
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Cabrera
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, Michigan 48109, United States.
authors.forename: Noam I
authors.initials: NI
authors.lastname: Saper
authors.affiliation: Department of Chemistry, University of Michigan, 930 N. University Ave, Ann Arbor, Michigan 48109, United States.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Sanford
mesh_terms: D000588:Amines / Q000737:chemistry*; D002244:Carbon / Q000737:chemistry*; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D006571:Heterocyclic Compounds / Q000737:chemistry; D006859:Hydrogen / Q000737:chemistry*; D009584:Nitrogen / Q000737:chemistry; D010165:Palladium / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis / Q000737:chemistry; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D000068580:Varenicline / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D000588:Amines; D006571:Heterocyclic Compounds; D004364:Pharmaceutical Preparations; D010880:Piperidines; D010165:Palladium; D002244:Carbon; D006859:Hydrogen; D009584:Nitrogen; D000068580:Varenicline