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.

Figure 1. Relevance of alicyclic amines and strategies for their late stage functionalization

a, Representative pharmaceutical agents containing alicyclic amines. b, Previous synthetic approaches for the late-stage functionalization of alicyclic amines. R, R¹, generic substituent; FG, new functional group. c, Proposed approach for late stage transannular C–H functionalization of alicyclic amines.

Figure 2. Design and realization of transannular C–H activation of alicyclic amines

a, Conceptual approach to transannular C-H arylation of via a bicyclo[2.2.1]metallacycle intermediate. [Pd], Pd complex. b, Evolution of model substrate 2 to 3. C₇F₇, 4-(CF₃)C₆F₄. c, Reaction optimization using 4-iodobiphenyl (Aryl-I). t-AmylOH, 2-methyl-2-butanol; nd, not detected. All yields determined by gas chromatography (GC). See supplementary information for full details.

Figure 3. Transannular C–H arylation of 3-azabicyclo[3.1.0]hexane core

a, Scope of C–H arylation with respect to the aryl iodide. b, Relevant steps in overall transformation: installation of directing group, C–H arylation and SmI₂-mediated removal of directing group (Aryl = biphenyl). PivCl, pivaloyl chloride; TEA, triethylamine. c, C–H arylation applied to amitifiadine. All yields are reported for pure isolated material. †, Reaction was conducted using 20 equiv of PhBr; yield determined by GC. ‡, Reaction was conducted under modified conditions. See supplementary information for full details.

Figure 4. Transannular C–H arylation of alicyclic amines

a, Scope of the C–H arylation reaction with respect to the amine. b, Application of this reaction to the derivatization of varenicline. c, Application of this reaction to the derivatization of cytisine. Yields are reported for pure isolated products. †, Reaction was conducted under modified conditions. See supplementary information for full details.