Over the past decade, the most significant, conceptual advances in the field of fluorination were enabled most prominently by organo- and transition-metal catalysis. The most challenging transformation remains the formation of the parent C-F bond, primarily as a consequence of the high hydration energy of fluoride, strong metal-fluorine bonds, and highly polarized bonds to fluorine. Most fluorination reactions still lack generality, predictability, and cost-efficiency. Despite all current limitations, modern fluorination methods have made fluorinated molecules more readily available than ever before and have begun to have an impact on research areas that do not require large amounts of material, such as drug discovery and positron emission tomography. This Review gives a brief summary of conventional fluorination reactions, including those reactions that introduce fluorinated functional groups, and focuses on modern developments in the field.

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Introduction of Fluorine and Fluorine-Containing Functional Groups

Visible-light photocatalysis has evolved over the last decade into a widely used method in organic synthesis. Photocatalytic variants have been reported for many important transformations, such as cross-coupling reactions, α-amino functionalizations, cycloadditions, ATRA reactions, or fluorinations. To help chemists select photocatalytic methods for their synthesis, we compare in this Review classical and photocatalytic procedures for selected classes of reactions and highlight their advantages and limitations. In many cases, the photocatalytic reactions proceed under milder reaction conditions, typically at room temperature, and stoichiometric reagents are replaced by simple oxidants or reductants, such as air, oxygen, or amines. Does visible-light photocatalysis make a difference in organic synthesis? The prospect of shuttling electrons back and forth to substrates and intermediates or to selectively transfer energy through a visible-light-absorbing photocatalyst holds the promise to improve current procedures in radical chemistry and to open up new avenues by accessing reactive species hitherto unknown, especially by merging photocatalysis with organo- or metal catalysis.

Visible-Light Photocatalysis: Does It Make a Difference in Organic Synthesis?

Metal-catalyzed carbon-sulfur bond formation.

The first enantioselective, organocatalytic α-trifluoromethylation and α-perfluoroalkylation of aldehydes have been accomplished using a readily available iridium photocatalyst and a chiral imidazolidinone catalyst. A range of α-trifluoromethyl and α-perfluoroalkyl aldehydes were obtained from commercially available perfluoroalkyl halides with high efficiency and enantioselectivity. The resulting α-trifluoromethyl aldehydes were subsequently shown to be versatile precursors for the construction of a variety of enantioenriched trifluoromethylated building blocks.

Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox Organocatalysis

This Minireview highlights recent developments in radical trifluoromethylation reactions. The trifluoromethyl group belongs to the privileged moieties in medicinal chemistry. Many drugs and drug candidates contain a trifluoromethyl substituent. Also in agrochemicals, the CF3 moiety often appears. The present article addresses the radical trifluoromethylation of alkenes and arenes mainly focussing on recent achievements. However, important earlier work in this field is also covered.

A "Renaissance" in radical trifluoromethylation

Pyridine undergoes addition of pinacolborane at 50 °C in the presence of a rhodium catalyst, giving N-boryl-1,2-dihydropyridine in a high yield. The selective 1,2-hydroboration also takes place in the reactions of substituted pyridines. In the reaction of 3-substituted pyridines, 3-substituted N-boryl-1,2-dihydropyridines are formed regioselectively.

Regioselective Synthesis of 1,2-Dihydropyridines by Rhodium-Catalyzed Hydroboration of Pyridines

The esters (I) reacts with the 1,1-dibromoalkanes (II) in the presence of zinc-dust and titanium tetrachloride, yielding the 1-alkenyl ethers (III) with predominance of the Z-isomers.

Alkylidenation of Ester Carbonyl Groups by means of a Reagent Derived from RCHBr2, Zn, TiCl4, and TMEDA. Stereoselective Preparation of (Z)-Alkenyl Ethers

Triethylborane-induced stereoselective radical addition of perfluoroalkyl iodides to acetylenes

A variety of trialkylborane-induced reactions were examined for the preparation of the α-carbonyl radicals: (1) addition of alkyl radical to methyl vinyl ketone, (2) reduction of α-halo ketone, and (3) intramolecular radical addition to α,β-unsaturated carbonyl moiety. Trialkylborane reacted with α-carbonyl radicals to give boron enolates. The resulting boron enolates were efficiently trapped by carbonyl compounds to give β-hydroxy ketones in good yields.

Trialkylborane as an initiator and terminator of free radical reactions. Facile routes to boron enolates via α-carbonyl radicals and aldol reaction of boron enolates

The regioselectivity in the addition of silylboronic esters to terminal alkynes can be switched by the choice of phosphorus ligands on the palladium catalysts. The silaboration proceeds with normal regisoselectivity in the presence of (η3-C3H5)Pd(PPh3)Cl (1.0 mol %) to give 1-boryl-2-silyl-1-alkenes in high yields. In sharp contrast, selective formation of the inverse regioisomers, 2-boryl-1-silyl-1-alkenes, takes place when the reaction is carried out with a palladium catalyst bearing P(t-Bu)2(biphenyl-2-yl). A reaction mechanism for the change of regioselectivity that involves reversible insertion/β-boryl elimination steps is proposed.

Koichiro Oshima

Papers

Regioselective Synthesis of 1,2-Dihydropyridines by Rhodium-Catalyzed Hydroboration of Pyridines

Alkylidenation of Ester Carbonyl Groups by means of a Reagent Derived from RCHBr2, Zn, TiCl4, and TMEDA. Stereoselective Preparation of (Z)-Alkenyl Ethers

Triethylborane-induced stereoselective radical addition of perfluoroalkyl iodides to acetylenes

Trialkylborane as an initiator and terminator of free radical reactions. Facile routes to boron enolates via α-carbonyl radicals and aldol reaction of boron enolates

Switch of Regioselectivity in Palladium-Catalyzed Silaboration of Terminal Alkynes by Ligand-Dependent Control of Reductive Elimination