Interaction between Divalent Copper Fluoride and Carboxamide Group Enabling Stereoretentive Fluorination of Tertiary Alkyl Halides

Abstract

Herein, we report a copper‐catalyzed stereospecific fluorination involving CsF and α‐bromocarboxamides as tertiary alkyl sources that, unlike traditional stereospecific routes involving stereoinversive SN2 reactions, proceeds with retention of stereochemistry. The developed stereospecific Cu‐catalyzed reaction is among the most efficient methods for synthesizing fluorinated molecules that possess highly congested stereogenic carbon centers. Mechanistic studies revealed that the combined reactivity of CuF2 and Cs salt is essential for completing the catalytic cycle. Our catalytic system underwent fluorination exclusively with tertiary alkyl bromides and did not react with primary alkyl bromides, indicating that this stereospecific fluorination methodology is suitable for synthesizing fluorinated building blocks possessing stereo‐defined F‐containing tertiary carbon stereogenic center.

Recent Advances in Nonprecious Metal Catalysis

“…16 Nishikata and co-workers recently reported a stereospecific CuBr 2 /dtbpy-catalyzed nucleophilic fluorination of tertiary alkyl bromides that proceeds with retention of configuration (Scheme 14). 17 Several N-and P-donor ligands were evaluated, and the enantiospecificity (es) was highly liganddependent. The reaction was most general for dialkyl bromocarboxamide or alkyl aryl bromocarboxamide derivatives.…”