Mild and catalytic electrocyclizations of heptatrienyl anions.

We report the synthesis of functionalized cycloheptanes by thermal electrocyclization of heptatrienyl anions under mild conditions. In addition, we disclose the first examples of this electrocyclization manifold conducted under catalytic conditions. Previously, electrocyclization of heptatrienyl systems required formation of anions with a strong base, resulting in limited functional group compatibility. We demonstrate that polarization of heptatrienyl anions using strategically positioned electron-withdrawing groups lowers the energy landscape of the reaction by stabilizing both the acyclic heptatrienyl anion and cycloheptadienyl product. Divergent reactivity is observed between aliphatic and aromatic substrates, with the latter requiring only catalytic amounts of base for complete conversion. This can be rationalized by the relative stability of the acyclic and cyclic anions and their ability to participate in a chain reaction process.

Soft Fluorination of 4-Alkylpyridines.

We report the mild and selective mono- and difluorination of 4-alkylpyridines. The process involves soft-dearomatization of pyridines to the corresponding alkylidene dihydropyridines and treatment with Selectfluor. The reaction tolerates a broad range of functional groups, including those bearing acidic and weak C-H bonds. In addition, selective fluorination of 4-alkylpyridines attached to 2-alkylpyridines and 2-alkylpyrimidines can be achieved in good yields, but a 4-alkylpyridine tethered to a 4-alkylpyrimidine is fluorinated at both heterobenzylic positions.

Mild Installation of Piperidines on 4-Alkylpyridines.

We report a mild method for the synthesis of scaffolds bearing 4-pyridine and 4-piperidine moieties joined by a substituted methylene group. The method exploits the latent nucleophilicity of 4-alkylpyridines and the inherent electrophilicity of pyridines. 4-Alkylpyridines are transformed into nucleophilic alkylidene dihydropyridines (ADHPs) through a soft enolization approach using triethyl amine and chloroformate reagents. HCl is used to promote the addition of ADHPs to pyridine, yielding an adduct bearing pyridine and protected dihydropyridine fragments. Transfer hydrogenation delivers the desired compounds in good yields.

Pyridylic anions are soft nucleophiles in the palladium-catalyzed C(sp3)-H allylation of 4-alkylpyridines.

We report a mild palladium-catalyzed method for the selective allylation of 4-alkylpyridines in which highly basic pyridylic anions behave as soft nucleophiles. This method exploits alkylidene dihydropyridines, which are semi-stable intermediates readily formed using a 'soft-enolization' approach, in a new mechanistic manifold for decarboxylative allylation. Notably, the catalytic generation of pyridylic anions results in a substantially broader functional group tolerance compared to other pyridine allylation methods. Experimental and theoretical mechanistic studies strongly suggest that pyridylic anions are indeed the active nucleophiles in these reactions, and that they participate in an outer-sphere reductive elimination step. This finding establishes a new pK a boundary of 35 for soft nucleophiles in transition metal-catalyzed allylations.