Palladium-catalysed transannular C–H functionalization of alicyclic amines

Abstract

The discovery of pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. Carbon-hydrogen bonds are present in almost all pharmaceutical agents. As such, the development of selective, rapid, and efficient methods for converting carbon-hydrogen bonds into new chemical entities has the potential to dramatically streamline pharmaceutical development1,2,3,4. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, including treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukemia (alvocidib), schizophrenia (risperidone, belaperidone), and nicotine addiction (cytisine and varenicline)5. However, existing methods for the C–H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited 6,7. Here we report a new approach to selectively manipulate the carbon–hydrogen bonds of alicyclic amines at sites remote to nitrogen. Our reaction leverages the boat conformation of the substrates to achieve the palladium-catalyzed amine-directed conversion of C–H bonds to C–C bonds on various alicyclic amine scaffolds. This approach is applied to the synthesis of novel derivatives of several bioactive molecules, including the top-selling smoking cessation drug varenicline (Chantix®). We anticipate that this method should prove broadly useful in medicinal chemistry.

Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer

“…[37] The4 -position of piperidine 72 can be arylated after the nitrogen atom has been alkylated and linked to ap erfluorinated amide,adirecting group first introduced by Yu and co-workers (see Scheme 19), to afford its derivative 73.…”

Native functionality in triple catalytic cross-coupling: sp 3 C–H bonds as latent nucleophiles

“…Among the well-established challenges with sp 3 C–H bond functionalization, regioselectivity is perhaps preeminent, given that organic molecules incorporate a diverse combination of methyl, methylene, and/or methine groups. Several elegant methodologies have navigated this question via the use of directing groups to accomplish selective sp 3 C–H bond functionalization (9–13), or more recently by focusing on the use of inductive effects to deactivate C–H bonds (14). Enzymes accomplish selective sp 3 C–H bond functionalization by taking advantage of the diverse electronic and enthalpic characteristics of carbon–hydrogen bonds found within complex organic molecules (15).…”

Ruthenium(II)-catalysed remote C–H alkylations as a versatile platform to meta-decorated arenes

“…Since the substrates of interest display a variety of C–H bonds with close dissociation energies, achieving positional selectivity in intermolecular C–H transformations is paramount1112131415. Thus, chelation assistance has proven particularly instrumental for proximity-induced ortho -C–H functionalizations16171819.…”