Transition‐Metal‐Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C−C Bond Formation

Abstract

Alkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and pKa of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C−F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C−C bond formation (monofluoroalkylation) are inherently convergent and complexity‐generating, they have been studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition‐metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.

Catalytic alkene skeletal modification for the construction of fluorinated tertiary stereocenters

“…Catalytic methodologies based on (i) fluorination of alkenes, enol(ates), phenols and C–H bonds with electrophilic fluorinating reagents 3 or in (ii) transformations of fluorine-containing starting materials, 4 can be considered the most developed approaches for the regio- and enantioselective construction of fluorinated tertiary stereocenters. However, they respectively employ electrophilic fluorinating reagents – which are derived from fluorine gas – and use pre-functionalized fluorinated starting materials that could need multistep synthetic sequences.…”

Tetrasubstituted Carbon Stereocenters via Copper-Catalyzed Asymmetric Sonogashira Coupling Reactions with Cyclic gem-Dihaloketones and Tertiary α-Carbonyl Bromides

“…Geminal dihalides are versatile building blocks for constructing valuable monohalo derivatives through transition-metal-catalyzed selective carbon–carbon cross-coupling reactions. However, the catalytic and asymmetric coupling has been studied less, possibly due to the lack of a suitable catalytic system . Fu et al reported the enantioselective formation of tertiary alkyl fluorides through nickel-catalyzed Negishi couplings of racemic α-halo-α-fluoroketones in good yields and excellent ee .…”

A General and Efficient Solution to Monofluoroalkylation: Divergent Synthesis of Aliphatic Monofluorides with Modular Synthetic Scaffolds

“…To address the issues and challenges in direct C−F bond formation, we sought inspiration from the retrosynthetic analysis of aliphatic fluorides where the strategical disconnection of C−C bond would result in an alternative path via transition metal catalyzed C−C(R f ) cross‐couplings [27–32] . Compared with direct C−F bond formation, C−C couplings via transition metal catalysis could offer a facile, efficient, and highly selective approach to “diversity‐oriented” syntheses (DOS) of aliphatic fluorides under mild conditions with excellent functional group tolerance [33, 34] . However, the conventional fluorine‐containing raw materials and precursors were either difficult to be handled with due to their often gaseous nature (H 2 CFX, etc.…”