Mechanochemical Synthesis of Aryl Fluorides by Using Ball Milling and a Piezoelectric Material as the Redox Catalyst.

Aryl fluorides are important structural motifs in many pharmaceuticals. Although the Balz-Schiemann reaction provides an entry to aryl fluorides from aryldiazonium tetrafluoroborates, it suffers from drawbacks such as long reaction time, high temperature, toxic solvent, toxic gas release, and low functional group tolerance. Here, we describe a general method for the synthesis of aryl fluorides from aryldiazonium tetrafluoroborates using a piezoelectric material as redox catalyst under ball milling conditions in the presence of Selectfluor. This approach effectively addresses the aforementioned limitations. Furthermore, the piezoelectric material can be recycled multiple times. Mechanistic investigations indicate that this fluorination reaction may proceed via a radical pathway, and Selectfluor plays a dual role as both a source of fluorine and a terminal reductant.

Phosphinylation of Non-activated Aryl Fluorides through Nucleophilic Aromatic Substitution at the Boundary of Concerted and Stepwise Mechanisms.

Non-activated aryl fluorides reacted with potassium diorganophosphinites through a nucleophilic aromatic substitution (SN Ar) reaction. Remarkably, both electron-neutral and electron-rich aryl fluorides participated in the reaction with substantially stabilized anionic P nucleophiles to form the corresponding tertiary phosphine oxides. Quantum chemical calculations suggested a nucleophile-dependent mechanism that involves both concerted and stepwise SN Ar reaction pathways.

Nucleophilic Aromatic Substitution of Unactivated Aryl Fluorides with Primary Aliphatic Amines by Organic Photoredox Catalysis.

In this work, a mild and transition-metal-free approach for the nucleophilic aromatic substitution (SN Ar) of unactivated fluoroarenes with primary aliphatic amines to form aromatic amines is reported. This reaction is facilitated by the formation of cationic fluoroarene radical intermediates in the presence of an acridinium-based organic photocatalyst under blue-light irradiation. Various electron-rich and electron-neutral fluoroarenes are competent electrophiles for this transformation. A wide range of primary aliphatic amines, including amino acid esters, dipeptides, and linear and branched amines are suitable nucleophiles. The synthetic utility of this protocol is demonstrated by the late-stage functionalization of several complex drug molecules.

N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,ß-Unsaturated Amides.

Concerted nucleophilic aromatic substitution (CSN Ar) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CSN Ar reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of acrylamides that contain a 2-fluorophenyl group on the nitrogen through a CSN Ar reaction. By using this catalytic method, it is possible to synthesize an array of quinolin-2-one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (Cipso -Cß )→ σ*(Cipso -F) interaction critically contributes to the stabilization of the transition state for the cyclization.

Hypervalent Iodine(III)-Catalyzed Balz-Schiemann Fluorination under Mild Conditions.

An unprecedented hypervalent iodine(III) catalyzed Balz-Schiemann reaction is described. In the presence of a hypervalent iodine compound, the fluorination reaction proceeds under mild conditions (25-60 °C), and features a wide substrate scope and good functional-group compatibility.

Carbon-Fluorine Reductive Elimination from Nickel(III) Complexes.

We report a C-F reductive elimination from a characterized first-row aryl metal fluoride complex. Reductive elimination from the presented nickel(III) complexes is faster than C-F bond formation from any other characterized aryl metal fluoride complex.

Metal-Mediated Halogen Exchange in Aryl and Vinyl Halides: A Review.

Halogenated arenes and alkenes are of prime importance in many areas of science, especially in the pharmaceutical, agrochemical, and chemical industries. While the simplest ones are commercially available, some of them are still hardly accessible depending on their substitution patterns and the nature of the halogen atom. Reactions enabling the selective and efficient replacement of the halogen atom of an aryl or alkenyl halide by another one, lighter, or heavier, are therefore of major importance since they can be used for example to turn a less reactive aryl/alkenyl chloride into the more reactive iodinated derivatives or, in a reversed sense, to block an undesired reactivity, for late-stage modifications or for the introduction of a radionuclide. If some halogen exchange reactions are possible with activated substrates, they usually require catalysis with metal complexes. Remarkably efficient processes have been developed for metal-mediated halogen exchange in aryl and vinyl halides: they are overviewed, in a comprehensive manner, in this review article.