Via conversion to Katritzky pyridinium salts, alkyl amines can now be used as alkyl radical precursors for a range of deaminative functionalization reactions. The key step of all of these methods is single-electron reduction of the pyridinium ring, which triggers C−N bond cleavage. However, little has been done to understand how the precise nature of the pyridinium influences these events. Using a combination of synthesis, computation, and electrochemistry, this study delineates the steric and electronic effects that substituents have on the canonical steps and the overall process. Depending on the approach taken, consideration of both the reduction and the subsequent radical dissociation may be necessary. Whereas the electronic effects on these steps work in opposition to each other, the steric effects are synergistic, with larger substituents favoring both steps. This understanding provides a framework for future design of pyridinium salts to match the mode of catalysis or activation.
The use of a simple stilbene ligand
has enabled a stereospecific
Suzuki–Miyaura cross-coupling of tertiary benzylic carboxylates,
including those lacking naphthyl substituents. This method installs
challenging all-carbon diaryl quaternary stereocenters in good yield
and ee and represents an important breakthrough in the “naphthyl
requirement” that pervades stereospecific cross-couplings involving
enantioenriched electrophiles.
Highly enantioenriched benzylic and allylic amines and alcohols are readily available via asymmetric synthesis and in complex natural products. The development of mild, nickel-catalyzed crosscouplings of their derivatives has advanced the tools available for the preparation of a range of highly enantioenriched products, including those with quaternary stereocenters. This perspective focuses on crosscouplings with convenient and functional-group-tolerant organoboron reagents and highlights the discoveries of activating groups and conditions that have led to high-yielding and highly stereospecific reactions. Emphasis is placed on a mechanistic understanding, particularly with regard to controlling inversion vs retention pathways. Limitations and opportunities for future developments are also highlighted.
Methyl groups can imbue valuable
properties in organic molecules,
often leading to enhanced bioactivity. To enable efficient installation
of methyl groups on simple building blocks and in late-stage functionalization,
a nickel-catalyzed reductive coupling of secondary Katritzky alkylpyridinium
salts with methyl iodide was developed. When coupled with formation
of the pyridinium salt from an alkyl amine, this method allows amino
groups to be readily transformed to methyl groups with broad functional
group and heterocycle tolerance.
A deaminative
reaction of Katritzky alkylpyridinium salts and sulfinimines
has been developed to deliver enantiopure α-chiral amines. The
success of this method relied on the discovery of a thermally promoted
deamination via single-electron transfer of an anion−π
complex of the alkylpyridinium cation with potassium carbonate. This
method boasts excellent diastereoselectivity over the α-stereocenter
as well as broad functional group and heterocycle tolerance.
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