MRV

The merger of hydrogen atom transfer and Sulfinyl-Smiles rearrangement enables the asymmetric arylation of C(sp³)−H bonds in remote position to the double bond under photoredox conditions. Various chiral α-arylated amides are obtained with up to >99 : 1 er where the sulfinamido groups dictates the stereochemical outcome.

Abstract

An efficient asymmetric remote arylation of C(sp³)−H bonds under photoredox conditions is described here. The reaction features the addition radicals to a double bond followed by a site-selective radical translocation (1,n-hydrogen atom transfer) as well as a stereocontrolled aryl migration via sulfinyl-Smiles rearrangement furnishing a wide range of chiral α-arylated amides with up to >99 : 1 er. Mechanistic studies indicate that the sulfinamide group governs the stereochemistry of the product with the aryl migration being the rate determining step preceded by a kinetically favored 1,n-HAT process.

We have developed a Pd-catalyzed Z-retentive allylic substitution reaction for the first time. The utilization of a sterically bulky phosphoramidite ligand enables the nucleophilic attack step to proceed prior to the π-σ-π isomerization process of the π-allyl-Pd intermediate. This synthetic protocol displays a general scope for both nucleophiles and Z-allyl electrophilic precursors. In addition, an enantioselective variant has been demonstrated for the synthesis of highly diastereo- and enantioenriched cyclic ketones possessing a Z-alkene moiety starting from Z-allyl carbonates.

Nature Chemistry, Published online: 01 March 2024; doi:10.1038/s41557-024-01472-6

Although generally perceived as an old-fashioned and unselective tool to build molecules, the photochemistry community is now re-discovering the power of UV light and is using key mechanistic information to develop new catalytic processes driven by visible light. This Perspective discusses the progress and impact of UV light in organic synthesis.

Photocatalytic reactions with a reductive radical-polar crossover (RRPCO) involve intermediates with carbanionic reactivity. These are best described as free carbanions. Reactions with such carbanions depend on the balance between their nucleophilicity and basicity. Deprotonation of reaction partners and common organic solvents such as acetonitrile, dimethylformamide, and dimethylsulfoxide is the main competing reaction to nucleophilic addition.

Abstract

Photocatalytic reactions involving a reductive radical-polar crossover (RRPCO) generate intermediates with carbanionic reactivity. Many of these proposed intermediates resemble highly reactive organometallic compounds. However, conditions of their formation are generally not tolerated by their isolated organometallic versions and often a different reactivity is observed. Our investigations on their nature and reactivity under commonly used photocatalytic conditions demonstrate that these intermediates are indeed best described as free, superbasic carbanions capable of deprotonating common polar solvents usually assumed to be inert such as acetonitrile, dimethylformamide, and dimethylsulfoxide. Their basicity not only towards solvents but also towards electrophiles, such as aldehydes, ketones, and esters, is comparable to the reactivity of isolated carbanions in the gas-phase. Previously unsuccessful transformations thought to result from a lack of reactivity are explained by their high reactivity towards the solvent and weakly acidic protons of reaction partners. An intuitive explanation for the mode of action of photocatalytically generated carbanions is provided, which enables methods to verify reaction mechanisms proposed to involve an RRPCO step and to identify the reasons for the limitations of current methods.

Nature Catalysis, Published online: 23 February 2024; doi:10.1038/s41929-024-01118-3

Electrochemical cross-electrophile coupling with alkyl halides for the construction of C(sp3)–C(sp3) bonds is generally limited to activated alkyl halides. Now this approach is extended to coupling of unactivated alkyl halides using a nickel catalyst under mild conditions.

Phenols and naphthols are dearomatized to methoxycyclohexadienones under simple and robust electrochemical conditions, in a green way without chemical oxidants. The mechanism of the reaction is established using density functional theory calculations, which also explain the chemo- and regioselectivity for differently-substituted substrates.

Abstract

The electrochemical oxidative dearomatizing methoxylation of phenols and naphthols was developed. It provides an alternative route for the preparation of methoxycyclohexadienones, important and versatile synthetic intermediates, that eliminates the need for stoichiometric high-energy chemical oxidants and generates hydrogen as a sole by-product. The reaction proceeds in a simple constant current mode, in an undivided cell, and it employs standardized instrumentation. A collection of methoxycyclohexadienones derived from various 2,4,6-tri-substituted phenols and 1-substituted-2-naphthols was obtained in moderate to excellent yields. These include a complex derivative of estrone, as well as methoxylated dearomatized 1,1′-bi-2-naphthols (BINOLs). The mechanism of the reaction was subject to profound investigations using density functional theory calculations. In particular, the reactivity of two key intermediates, phenoxyl radical and phenoxenium ion, was carefully examined. The obtained results shed light on the pathway leading to the desired product and rationalize experimentally observed selectivities regarding a side benzylic methoxylation and the preference for the functionalization at the para over the ortho position. They also uncover the structure-selectivity relationship, inversely correlating the steric bulk of the substrate with its propensity to undergo the side-reaction. Moreover, the loss of stereochemical information from enantiopure BINOL substrates during the reaction is rationalized by the computations.

Building on the pioneering works using imines to form metallacycle with transition metals, recent developments have realized the potential of using transient directing group (TDG) to direct C−H functionalization. This article discusses factors defining a transient directing group and strategies to achieve catalytic processes with low directing group loading by highlighting recent advancements in this field.

Abstract

‘Transient’ C−H functionalization has emerged in recent years to describe the use of a dynamic linkage, often an imine, to direct cyclometallation and subsequent functionalization. As the field continues to grow in popularity, we consider the features that make an imine directing group transient. A transient imine should be i) formed dynamically in situ, ii) avoid discrete introduction or cleavage steps, and iii) offer the potential for catalysis in both the directing group and metal. This concept article contrasts transient imines with pioneering early studies of imines as directing groups for the formation of metallacycles and the use of preformed imines in C−H functionalization. Leading developments in the use of catalytic additives to form transient directing groups (as aldehyde or amine) are covered including selected highlights of the most recent examples of catalytic imine directed C−H functionalization with transition metals.

Nature Chemistry, Published online: 14 February 2024; doi:10.1038/s41557-024-01451-x

The mechanism for the oxidative addition of aryl halides to nickel(0)–phosphine complexes was proposed over four decades ago. Now, this elementary reaction, which occurs during common cross-coupling reactions, has been re-examined. Both one- and two-electron pathways occur, and their relative contribution depends on the electronic properties of the reaction partners.

Two Pd-catalyzed asymmetric [3+2] annulations are disclosed, providing a modular platform for the enantioselective synthesis of chiral thio-oxazolidinones. Preliminary mechanistic studies are performed to rationalize the observed enantio- and diastereo-controls.

Abstract

Organic molecules bearing chiral sulfur stereocenters exert a great impact on asymmetric catalysis and synthesis, chiral drugs, and chiral materials. Compared with acyclic ones, the catalytic asymmetric synthesis of thio-heterocycles has largely lagged behind due to the lack of efficient synthetic strategies. Here we establish the first modular platform to access chiral thio-oxazolidinones via Pd-catalyzed asymmetric [3+2] annulations of vinylethylene carbonates with sulfinylanilines. This protocol is featured by readily available starting materials, and high enantio- and diastereoselectivity. In particular, an unusual effect of a non-chiral supporting ligand on the diastereoselectivity was observed. Possible reaction mechanisms and stereocontrol models were proposed.

Ni-catalyzed decarboxylative C(sp³)−N cross-coupling of redox active ester and oxime esters was realized through electrochemical cathodic reduction. Mechanistic studies unveil a high-valent nickel species-driven reductive elimination pathway, rather than direct radical-radical coupling. The utility of this methodology was demonstrated through a broad scope (1°, 2°, 3° carboxylic acids) and late-stage functionalization of complex molecules.

Abstract

A new electrochemical transformation is presented that enables chemists to couple simple alkyl carboxylic acid derivatives with an electrophilic amine reagent to construct C(sp³)−N bond. The success of this reaction hinges on the merging of cooperative electrochemical reduction with nickel catalysis. The chemistry exhibits a high degree of practicality, showcasing its wide applicability with 1°, 2°, 3° carboxylic acids and remarkable compatibility with diverse functional groups, even in the realm of late-stage functionalization. Furthermore, extensive mechanistic studies have unveiled the engagement of alkyl radicals and iminyl radicals; and elucidated the multifaceted roles played by ⁱ Pr₂O, Ni catalyst, and electricity.

The transformation of alkenes into thianthrene-derived cationic electrophiles unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles.

Abstract

Oxidative alkene functionalization reactions are a fundamental class of complexity-building organic transformations. However, the majority of established approaches rely on electrophilic reagents that limit the diversity of groups that can be installed. Recent advances have established a new approach that instead relies on the transformation of alkenes into thianthrene-derived cationic electrophiles. These linchpin intermediates can be generated selectively and undergo a diverse array of mechanistically distinct reactions with abundant nucleophiles. Taken together, this unlocks a suite of net oxidative alkene transformations that have been elusive using conventional strategies. This Minireview describes these advances and is organized around the three distinct synthons formally accessible from alkenes via thianthrenation: 1) alkenyl cations; 2) vicinal dications; 3) allyl cations. Throughout the Minireview, we illustrate how thianthrenium salts address key limitations endemic to classic alkene-derived electrophiles and highlight the mechanistic origins of these distinctions wherever possible.

Utilizing readily available and cost-effective aryl halides, amines, and butadienes as starting materials, in conjunction with rac-BINAP and a Pd catalyst, we can efficiently synthesize highly valuable complex allylamines through a rapid one-step process enabled by photocatalysis.

Abstract

A visible-light-induced, three-component palladium-catalyzed 1,4-aminoarylation of butadienes with readily available aryl halides and aliphatic amines has been developed, affording allylamines with excellent E-selectivity. The reaction exhibits exceptional control over chemo-, regio-, and stereoselectivity, a broad substrate scope, and high functional group compatibility, as demonstrated by the late-stage functionalization of bioactive molecules. Mechanistic investigations are consistent with a photoinduced radical Pd(0)-Pd(I)-Pd(II)-Pd(0) Heck-Tsuji–Trost allylation cascade.

A room-temperature Cu-catalyzed C−O coupling method has been developed utilizing a new N ¹,N ²-diarylbenzene-1,2-diamine ligand. These reactions feature mild reaction conditions, no need to use excess alcohol, and a unique mechanism that does not feature rate-determining reductive elimination.

Abstract

We disclose the development of a Cu-catalyzed C−O coupling method utilizing a new N ¹,N ²-diarylbenzene-1,2-diamine ligand, L8. Under optimized reaction conditions, structurally diverse aryl and heteroaryl bromides underwent efficient coupling with a variety of alcohols at room temperature using an L8-based catalyst. Notably, the L8-derived catalyst exhibited enhanced activity when compared to the L4-based system previously disclosed for C−N coupling, namely the ability to functionalize aryl bromides containing acidic functional groups. Mechanistic studies demonstrate that C−O coupling utilizing L8 ⋅ Cu involves rate-limiting alkoxide transmetallation, resulting in a mechanism of C−O bond formation that is distinct from previously described Pd-, Cu-, or Ni-based systems. This lower energy pathway leads to rapid C−O bond formation; a 7-fold increase relative to what is seen with other ligands. The results presented in this report overcome limitations in previously described C−O coupling methods and introduce a new ligand that we anticipate may be useful in other Cu-catalyzed C-heteroatom bond-forming reactions.

An electrochemical cyclization is leveraged to forge the central 9-membered ring in the hybrid metabolites dragocins A−C. The route features several stereocontrolled reactions to address the stereotetrad of the pyrrolidine fragment and a penultimate decarboxylative chlorination and global deprotection to furnish both dragocins B and C. Dragocin A was prepared through simple methanolysis of dragocin C.

Abstract

The first total synthesis of dragocins A−C, remarkable natural products containing an unusual C4’ oxidized ribose architecture bridged by a polyhydroxylated pyrrolidine, is presented through a route featuring a number of uncommon maneuvers. Several generations towards the target molecules are presented, including the spectacular failure of a key C−H oxidation on a late-stage intermediate. The final route features rapid, stereocontrolled access to a densely functionalized pyrrolidine and an unprecedented diastereoselective oxidative electrochemical cyclization to forge the hallmark 9-membered ring. Preliminary studies suggest this electrochemical oxidation protocol is generally useful.

A general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It proceeds through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to undergo deoxygenative cross-couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.

Abstract

A general approach to the direct deoxygenative transformation of primary, secondary, and tertiary alcohols has been developed. It undergoes through phosphoranyl radical intermediates generated by the addition of exogenous iodine radical to trivalent alkoxylphosphanes. Since these alkoxylphosphanes are readily in situ obtained from alcohols and commercially available, inexpensive chlorodiphenylphosphine, a diverse range of alcohols with various functional groups can be utilized to proceed deoxygenative cross-couplings with alkenes or aryl iodides. The selective transformation of polyhydroxy substrates and the rapid synthesis of complex organic molecules are also demonstrated with this method.