As some of the oldest organic chemical reactions known, the ionic additions of elemental halogens such as bromine and chlorine to alkenes are prototypical examples of stereospecific reactions, typically delivering vicinal dihalides resulting from anti-addition. Whilst the invention of enantioselective variants is an ongoing challenge, the ability to overturn the intrinsic anti-diastereospecificity of these transformations is also a largely unsolved problem. In this Article, we describe the first catalytic, syn-stereospecific dichlorination of alkenes, employing a group transfer catalyst based on a redox-active main group element (i.e., selenium). Thus, with diphenyl diselenide (PhSeSePh) (5 mol %) as the pre-catalyst, benzyltriethylammonium chloride (BnEt3NCl) as the chloride source, and an N-fluoropyridinium salt as the oxidant, a wide variety of functionalized cyclic and acyclic 1,2-disubstituted alkenes, including simple allylic alcohols, deliver syn-dichlorides with exquisite stereocontrol. This methodology is expected to find applications in streamlining the synthesis of polychlorinated natural products such as the chlorosulfolipids.

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Although recent years have witnessed significant advances in the development of catalytic, enantioselective halofunctionalizations of alkenes, the related dihalogenation of olefins to afford enantioenriched vicinal dihalide products remains comparatively underdeveloped. However, the growing number of complex natural products bearing halogen atoms at stereogenic centers has underscored this critical gap in the synthetic chemist's arsenal. This Review highlights the selectivity challenges inherent in the design of enantioselective dihalogenation processes, and formulates a mechanism-based classification of alkene dihalogenations, including those that may circumvent the "classical" haliranium (or alkene-dihalogen π-complex) intermediates. A variety of metal and main group halide reagents that have been used for the dichlorination or dibromination of alkenes are discussed, and the proposed mechanisms of these transformations are critically evaluated. AbstractCatalysis of alkene dihalogenation , under different activation modes, with control over both the absolute and relative stereochemical course of dihalogen addition, is one of the most vexing problems in stereoselective synthesis. Dihalogenations that circumvent the "classical" haliranium (or alkene-dihalogen π complex) intermediates provide new and exciting opportunities for catalysis, potentially having broader implications for the design of stereoselective alkene difunctionalizations.

A practical, catalytic entry to α,α,α‐trisubstituted (α‐tertiary) primary amines by C−H functionalisation has long been recognised as a critical gap in the synthetic toolbox. We report a simple and scalable solution to this problem that does not require any in situ protection of the amino group and proceeds with 100 % atom‐economy. Our strategy, which uses an organic photocatalyst in combination with azide ion as a hydrogen atom transfer (HAT) catalyst, provides a direct synthesis of α‐tertiary amines, or their corresponding γ‐lactams. We anticipate that this methodology will inspire new retrosynthetic disconnections for substituted amine derivatives in organic synthesis, and particularly for challenging α‐tertiary primary amines.

The first systematic investigation of unactivated aliphatic sulfur compounds as electrophiles in transition metal-catalyzed cross-coupling are described. Initial studies focused on discerning the structural and electronic features of the organosulfur substrate which enable the challenging oxidative addition to the C(sp3)–S bond. Through extensive optimization efforts, an Fe(acac)3-catalyzed cross-coupling of unactivated alkyl aryl thio ethers with aryl Grignard reagents was realized, in which a nitrogen “directing group” on the S-aryl moiety of the thio ether served a critical role in facilitating the oxidative addition step. In addition, alkyl phenyl sulfones were found to be effective electrophiles in the Fe(acac)3-catalyzed cross-coupling with aryl Grignard reagents. For the latter class of electrophile, a thorough assessment of the various reaction parameters revealed a dramatic enhancement in reaction efficiency with an excess of TMEDA (8.0 equiv). The optimized reaction protocol was used to evaluate the scope of the method with respect to both the organomagnesium nucleophile and sulfone electrophile.

A range of substituted aryl epoxides undergo efficient ring-opening hydrofluorination upon treatment with 0.33 equiv of BF(3) x OEt(2) in CH(2)Cl(2) at -20 degrees C to give the corresponding syn-fluorohydrins, consistent with a mechanism involving a stereoselective S(N)1-type epoxide ring-opening process. The benzylic fluoride products of these reactions are valuable templates for further elaboration, as demonstrated by the preparation of a range of aryl-substituted beta-fluoroamphetamines.

Tailoring of the pre-catalyst, the oxidant and the arylsilane enables the first room-temperature, gold-catalysed, innate C-H arylation of heteroarenes. Regioselectivity is consistently high and, in some cases, distinct from that reported with palladium catalysis. Tolerance to halides and boronic esters, in both the heteroarene and silane partners, provides orthogonality to Suzuki-Miyaura coupling.

Catalytic, intermolecular hydroaminoalkylation (HAA) of styrenes provides a powerful disconnection for pharmacologically relevant γ-arylamines, but current methods cannot utilize unprotected primary alkylamines as feedstocks. Metal-catalyzed HAA protocols are also highly sensitive to α-substitution on the amine partner, and no catalytic solutions exist for α-tertiary γ-arylamine synthesis via this approach. We report a solution to these problems using organophotoredox catalysis, enabling a direct, modular, and sustainable preparation of α-(di)substituted γ-arylamines, including challenging electron-neutral and moderately electron-rich aryl groups. A broad range of functionalities are tolerated, and the reactions can be run on multigram scale in continuous flow. The method is applied to a concise, protecting-group-free synthesis of the blockbuster drug Fingolimod, as well as a phosphonate mimic of its in vivo active form (by iterative α-C–H functionalization of ethanolamine). The reaction can also be sequenced with an intramolecular N -arylation to provide a general and modular access to valuable (spirocyclic) 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydronaphthyridines. Mechanistic and kinetic studies support an irreversible hydrogen atom transfer activation of the alkylamine by the azidyl radical and some contribution from a radical chain. The reaction is photon-limited and exhibits a zero-order dependence on amine, azide, and photocatalyst, with a first-order dependence on styrene.