Highly selective conjugate additions of Grignard reagents to cyclic and linear enones catalyzed by recyclable heterogeneous polysaccharide/nanocopper catalysts are disclosed. The method also allows the synthesis of ketones with an all-carbon quaternary center. When integrated with catalytic asymmetric tandem reactions using enals and β-ketoesters, it yields chiral β,δ-disubstituted ketones with high stereoselectivity.

Herein, we present a highly efficient allylic substitution of carbonates with Grignard reagents using a reusable cellulose-supported nanocopper catalyst. This approach highlights the first instance of heterogeneous catalysis for the cross-coupling of allylic alcohol substrates with Grignard reagents. The method features high yields, excellent regioselectivity, and complete chirality transfer.

Herein, we disclose a convenient protocol for the α-diarylation of carbon nucleophiles to yield heavily functionalized quaternary products. Diaryliodonium salts are utilized to transfer both aryl groups under transition-metal-free conditions, which enables an atom-efficient and high-yielding method with broad functional group tolerance. The methodology is amenable to a wide variety of carbon nucleophiles and can be utilized in late-stage functionalization of complex arenes. Furthermore, it is compatible with a new class of zwitterionic iodonium reagents, which gives access to phenols with an ortho-quaternary center. The diarylated products bear an ortho-iodo substituent that can be utilized in further transformations, including the formation of novel, functionalized six-membered cyclic iodonium salts.

Our group has reported several one-pot protocols for the synthesis of diaryliodonium salts, which have been recognized as attractive multi-purpose reagents in areas ranging from organic synthesis to materials chemistry. Over the years, we have identified limitations in the published protocols concerning synthesis of mixed electron-rich and electron-poor, as well as highly electron-poor diaryliodonium salts, as the corresponding starting materials are either too reactive or too unreactive. In this update, we discuss the underlying limitations concerning the stability and reactivity of the involved reagents and provide strategies to overcome these challenges through updated synthetic protocols. 

ORIGIN

Hypervalent bromine(III) reagents exhibit superior electrophilic reactivity compared with their iodine analogs. Recently, Wencel-Delord and coworkers described a strategy for the synthesis of cyclic bromonium salts and their utility as efficient arylating agents via aryne intermediates in the presence of a weak base.

REACTION MECHANISM

Aryl transfer reactions involving hypervalent halogen(III) reagents enable access to functionalized nucleophiles, and efficient methodology for arylations with diaryliodonium salts has been developed for a range of nucleophiles. Diarylbromonium salts are much less utilized, mainly due to instability and synthesis problems. However, transition metal-free C–O and C–N couplings involving cyclic bromonium(III) salts were recently reported under mild conditions. With carboxylates, exclusive meta- or ortho- selectivity was observed depending on the ring substitution pattern. The use of amine nucleophiles resulted in moderate to high regioselectivity in favor of the meta-substituted products.The reaction was found to proceed by deprotonation of bromonium salt A with simultaneous β-elimination of the excellent bromine(III) leaving group, leading to aryne B. Subsequent meta-selective nucleophilic attack by carboxylate C generates anionic intermediate D, which is either protonated by a new molecule of A in a possible autocatalytic process, or by the formed bicarbonate, releasing product E.Bromonium salts display greater reactivity and electrophilicity than the iodine analogs. Arylation of carboxylic acids with the latter proceeds regiospecifically at increased temperatures, whereas aryne formation is quite uncommon. Aryne intermediates have been utilized in cycloadditions and mechanistic studies from our group suggest that aryne formation also takes place in transition metal-free O-arylations of aliphatic alcohols with electron-rich diaryliodonium salts, resulting in regioisomeric product mixtures. Cyclic diaryliodonium salts are less reactive and their transformations generally require transition metal catalysis, as exemplified by the ortho-functionalization with carboxylic acids.

Efficient protocols for accessing iodo-implanted diaryl and aryl(vinyl) sulfides have been developed using iodonium salts as reactive electrophilic arylation and vinylation reagents. The reactions take place under transition metal-free conditions, employing odorless and convenient sulfur reagents. A wide variety of functional groups are tolerated in the S-diarylation, leading to the regioselective late-stage application of several heterocycles and drug molecules under mild reaction conditions. A novel S-difunctionalization pathway was discovered using vinyliodonium salts, which proceeds under additive-free reaction conditions and grants excellent stereoselectivity in the synthesis of (aryl)vinyl sulfides. A one-pot strategy combining transition metal-free diarylation and subsequent reduction provided facile access to electron-rich thioanilines and a direct synthesis of a potential drug candidate derivative. The retained iodo group allows a wide array of further synthetic transformations. Mechanistic insights were elucidated by isolating the key intermediate, and the relevant energy profile was substantiated by DFT calculations.