Xinlan A. F. Cook

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd ⁰ ‐catalyzed cross‐coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi‐step transformations. Here we introduce base‐activated, latent sulfinate reagents: β‐nitrile and β‐ester sulfones. We show that under the cross‐coupling conditions, these species generate the sulfinate salt in situ, which then undergo efficient palladium‐catalyzed desulfinative cross‐coupling with (hetero)aryl bromides to deliver a broad range of biaryls. These latent sulfinate reagents have proven to be stable through multi‐step substrate elaboration, and amenable to scale‐up.

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd⁰‐catalyzed cross‐coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi‐step transformations. Here we introduce base‐activated, latent sulfinate reagents: β‐nitrile and β‐ester sulfones. We show that under the cross‐coupling conditions, these species generate the sulfinate salt in situ, which then undergo efficient palladium‐catalyzed desulfinative cross‐coupling with (hetero)aryl bromides to deliver a broad range of biaryls. These latent sulfinate reagents have proven to be stable through multi‐step substrate elaboration, and amenable to scale‐up.

We propose the use of a bridged piperidine moiety as a phenyl bioisostere, leading to strongly improved drug like properties. This concept was applied to the discovery of γ-secretase modulators for the potential treatment of Alzheimer's disease.

Azine‐containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition‐metal‐catalysed cross‐coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds. However, 2‐pyridine organometallics are capricious coupling partners and 2‐pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki–Miyaura cross‐coupling reactions. The synthesis of pyridine‐containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2′‐bis‐pyridines are scarce. This Review focuses on the methods developed for the challenging coupling of 2‐pyridine nucleophiles with (hetero)aryl electrophiles, and ranges from traditional cross‐coupling processes to alternative nucleophilic reagents and novel main group approaches.

Azine‐containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition‐metal‐catalysed cross‐coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds. However, 2‐pyridine organometallics are capricious coupling partners and 2‐pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki–Miyaura cross‐coupling reactions. The synthesis of pyridine‐containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2′‐bis‐pyridines are scarce. This Review focuses on the methods developed for the challenging coupling of 2‐pyridine nucleophiles with (hetero)aryl electrophiles, and ranges from traditional cross‐coupling processes to alternative nucleophilic reagents and novel main group approaches.