19F- and 18F-Arene Deoxyfluorination via Organic Photoredox-Catalysed Polarity-Reversed Nucleophilic Aromatic Substitution.

Nucleophilic aromatic substitution (SNAr) is routinely used to install 19F- and 18F- in aromatic molecules, but is typically limited to electron-deficient arenes due to kinetic barriers associated with C-F bond formation. Here we demonstrate that a polarity-reversed photoredox-catalysed arene deoxyfluorination operating via cation radical-accelerated nucleophilic aromatic substitution (CRA-SNAr) enables the fluorination of electron-rich arenes with 19F- and 18F- under mild conditions, thus complementing the traditional arene polarity requirements necessary for SNAr-based fluorination. The utility of our radiofluorination strategy is highlighted by short reaction times, compatibility with multiple nucleofuges, and high radiofluorination yields, especially that of an important cancer positron emission tomography (PET) agent [18F]5-fluorouracil ([18F]FU). Taken together, our fluorination approach enables the development of fluorinated and radiofluorinated compounds that can be difficult to access by classical SNAr strategies, with the potential for use in the synthesis and discovery of PET radiopharmaceuticals.

Direct Aryl C-H Amination with Primary Amines Using Organic Photoredox Catalysis.

The direct catalytic C-H amination of arenes is a powerful synthetic strategy with useful applications in pharmaceuticals, agrochemicals, and materials chemistry. Despite the advances in catalytic C-H functionalization, the use of aliphatic amine coupling partners is limited. Described herein is the construction of C-N bonds, using primary amines, by direct C-H functionalization with an acridinium photoredox catalyst under an aerobic atmosphere. A wide variety of primary amines, including amino acids and more complex amines are competent coupling partners. Various electron-rich aromatics and heteroaromatics are useful scaffolds in this reaction, as are complex, biologically active arenes. We also describe the ability to functionalize arenes that are not oxidized by an acridinium catalyst, such as benzene and toluene, thus supporting a reactive amine cation radical intermediate.

Enantioselective (4+2) Annulation of Donor-Acceptor Cyclobutanes by N-Heterocyclic Carbene Catalysis.

Herein we report the enantioselective (4+2) annulation of donor-acceptor cyclobutanes and unsaturated acyl fluorides using N-heterocyclic carbene catalysis. The reaction allows a 3-step synthesis of cyclohexyl ß-lactones (25 examples) in excellent chemical yield (most ≥90 %) and stereochemical integrity (all >20:1 d.r., most ≥97:3 e.r.). Mechanistic studies support ester enolate Claisen rearrangement, while derivatizations provide functionalized cyclohexenes and dihydroquinolinones.

Influence of the N-Substituents on the Nucleophilicity and Lewis Basicity of N-Heterocyclic Carbenes.

The ability to modulate the nucleophilicity and Lewis basicity of N-heterocyclic carbenes is pivotal to their application as organocatalysts. Herein we examine the impact of the N-substituent on the nucleophilicity and Lewis basicity. Four N-substituents popular in NHC organocatalysis, namely, the N-2,6-(CH3O)2C6H3, N-Mes, N-4-CH3OC6H4, and N-tert-butyl groups, have been examined and found to strongly affect the nucleophilicity. Thus, the N-2,6-(CH3O)2C6H3 group provides the most nucleophilic imidazolylidene NHC reported and the N-tert-butyl group one of the least. This difference in nucleophilicity is reflected in the catalyst efficiency, as observed with a recently reported trienyl ester rearrangement.

Enantioselective N-Heterocyclic Carbene Catalyzed Diene Regenerative (4 + 2) Annulation.

An enantioselective N-heterocyclic carbene (NHC)-catalyzed diene regenerative (4 + 2) annulation has been achieved through the use of highly nucleophilic morpholinone-derived catalysts. The reaction proceeds with good to excellent yields, high enantioselectivity (most >92% ee), and good diastereoselectivity (most >7:1). The generality of the reaction is high, with 19 examples reported. The utility of the products has been examined with subsequent derivatization in Diels-Alder reactions using electron-poor dienophiles. Furthermore, interception of the proposed ß-lactone intermediate has been achieved, allowing the synthesis of compounds bearing four contiguous stereocenters with high levels of enantio- and diastereoselectivity.

N-Heterocyclic Carbene Catalyzed Synthesis of δ-Sultones via α,ß-Unsaturated Sulfonyl Azolium Intermediates.

A limited array of reactive intermediates have enabled a wealth of discoveries in N-heterocyclic carbene organocatalysis. In this study, the viability of α,ß-unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically, the (3+3) annulation of such species with the trimethylsilyl enol ethers of various 1,3-dicarbonyl compounds has been developed. This reaction provides access to a range of novel unsaturated δ-sultones (18 examples) in good yields (40-88 %) under mild reaction conditions. Mechanistic studies and the development of an enantioselective variant (55 % yield, 73:27 e.r.) support the intermediacy of an α,ß-unsaturated sulfonyl azolium species.

N-Heterocyclic carbene catalysed redox isomerisation of esters to functionalised benzaldehydes.

N-Heterocyclic carbene catalysed redox isomerisation with reduction about the carbonyl has been developed in the transformation of trienyl esters to tetrasubstituted benzaldehydes. The reaction proceeds in good to excellent yield, and in cases that provide 2,2'-biaryls, enantioselectivity is observed. Mechanistic studies demonstrate the intermediacy of a cyclohexenyl ß-lactone, while implicating formation of the homoenolate as turnover limiting.

Enantioselective all-carbon (4+2) annulation by N-heterocyclic carbene catalysis.

The enantioselective vinylogous Michael/aldol cascade is an underdeveloped approach to cyclohexenes. Herein we describe a highly enantioselective (most ≥ 98:2 er) and diastereoselective (all ≥ 15:1 dr) N-heterocyclic carbene catalyzed cycloisomerization of acyclic dienyl esters to cyclohexyl ß-lactones. Derivatizations avail cyclohexenes bearing four contiguous stereogenic centers, while mechanistic studies support olefin isomerization prior to cyclization.

Iodobenzene-catalyzed oxabicyclo[3.2.1]octane and [4.2.1]nonane synthesis via cascade C-O/C-C formation.

Iodobenzene-catalyzed 1,2-olefin functionalization via C-C and C-O bond formation has been achieved with electron rich aromatic groups and vinylogous esters acting as independent nucleophiles. The reaction provides oxabicyclo[3.2.1]octanes and [4.2.1]nonanes from commercially available 3-alkoxy cycohexen-2-ones in three steps.