A practical multicatalytic strategy that merges triplet energy-transfer (EnT) sensitization of di-tert-butyl peroxide with copper catalysis enables efficient O-and N-methylation of protic nucleophiles under mild and neutral conditions. A key design element of this system is the bifunctional reactivity of DTBP. Photoinduced O-O homolysis generates tert-butoxyl radicals, one of which undergoes β-methyl scission to furnish Me • with acetone as a low-boiling byproduct, while the complementary fragment participates in copper-mediated formation of alkoxide-type species (e.g., Cu-O t Bu) that promote in situ activation of O-H and N-H nucleophiles. This redox balanced, synchronized generation of a carbon-centered radical and a catalytic basic component obviates the need for externally added base and enables efficient heteroatom methylation at room temperature using low catalyst loadings. The transformation exhibits broad substrate scope, high functional-group tolerance, and excellent chemoselectivity governed by the interplay between nucleophile acidity and its coordination ability to copper. These features allow late-stage methylation of structurally complex molecules, including drug-like compounds, peptides, and nucleotides bearing acid-or base-sensitive functionalities. Mechanistic studies, supported by experimental and DFT investigations, reveal that methyl radicals are generated through EnT-sensitized peroxide activation, while the copper catalyst selectively orchestrates radical capture and C-heteroatom bond formation.

Vinyl boronates are highly valuable intermediates in chemical synthesis, extensively used in C‒C bond-forming reactions such as catalytic cross-coupling. Transition metal-catalyzed hydroboration of alkynes has emerged as a key method for synthesizing these building blocks. While classical approaches rely on noble metals like rhodium and iridium, copper-catalyzed hydroboration offers a sustainable and cost-effective alternative. This strategy utilizes bench-stable reagents under mild conditions, delivering highly stereoselective trans-vinylboronates. However, predicting regioselectivity re-mains a challenge due to the complex interplay of ligand structures, alkyne substitution patterns, and reaction conditions. To address this, we employed a combination of experimental data, high-throughput computational calculations, and ma-chine learning (ML) to develop predictive models for regioselectivity. Ligand and catalyst descriptors were derived from DFT calculations and literature databases, forming a robust dataset used to train ML algorithms. Further optimization proved effective in guiding experimental efforts by identifying promising ligands and improving hydroboration yields. This workflow integrates experimental and computational tools to achieve a stereocontrolled synthesis of substituted alkenyl boronates from alkynes. As a case study, we demonstrate the successful application of ML-guided optimization, reducing copper catalyst loading while improving yields and regioselectivity.

Stereochemically defined tetrasubstituted olefins are widespread structural elements of organic molecules and key intermediates in organic synthesis. However, flexible methods enabling stereodivergent access to E and Z isomers of fully substituted alkenes from a common precursor represent a significant challenge and are actively sought after in catalysis, especially those amenable to complex multifunctional molecules. Herein, we demonstrate that iterative dual-metal and energy transfer catalysis constitutes a unique platform for achieving stereodivergence in the difunctionalization of internal alkynes. The utility of this approach is showcased by the stereodivergent synthesis of both stereoisomers of tetrasubstituted β-boryl acrylates from internal alkynoates with excellent stereocontrol via sequential carboboration and photoisomerization. The reluctance of electron-deficient internal alkynes to undergo catalytic carboboration has been overcome through cooperative Cu/Pd-catalysis, whereas an Ir complex was identified as a versatile sensitizer that is able to photoisomerize the resulting sterically crowded alkenes. Mechanistic studies by means of quantum-chemical calculations, quenching experiments, and transient absorption spectroscopy have been applied to unveil the mechanism of both steps.

Artificial intelligence (AI) is an emerging technology that is revolutionizing the discovery of new materials. One key application of AI is virtual screening of chemical libraries, which enables the accelerated discovery of materials with desired properties. In this study, we developed computational models to predict the dispersancy efficiency of oil and lubricant additives, a critical property in their design that can be estimated through a quantity named blotter spot. We propose a comprehensive approach that combines machine learning techniques with visual analytics strategies in an interactive tool that supports domain experts' decision-making. We evaluated the proposed models quantitatively and illustrated their benefits through a case study. Specifically, we analyzed a series of virtual polyisobutylene succinimide (PIBSI) molecules derived from a known reference substrate. Our best-performing probabilistic model was Bayesian Additive Regression Trees (BART), which achieved a mean absolute error of 5.50±0.34 and a root mean square error of 7.56±0.47, as estimated through 5-fold cross-validation. To facilitate future research, we have made the dataset, including the potential dispersants used for modeling, publicly available. Our approach can help accelerate the discovery of new oil and lubricant additives, and our interactive tool can aid domain experts in making informed decisions based on blotter spot and other key properties.

A dual catalyst system based on ligand exchange of two diphosphine ligands possessing different properties in a copper complex has been devised to merge metal- and photocatalytic activation modes. This strategy has been applied to the formal anti-hydroboration of activated internal alkynes via a tandem sequence in which Cu/Xantphos catalyzes the B2pin2-syn-hydroboration of the alkyne whereas Cu/BINAP serves as a photocatalyst for visible light-mediated isomerization of the resulting alkenyl boronic ester. Photochemical studies by means of UV–vis absorption, steady-state and time-resolved fluorescence, and transient absorption spectroscopy have allowed characterizing the photoactive Cu/BINAP species in the isomerization reaction and its interaction with the intermediate syn-alkenyl boronic ester through energy transfer from the triplet excited state of the copper catalyst. In addition, mechanistic studies shed light into catalyst speciation and the interplay between the two catalytic cycles as critical success factors.

Compared to the tremendous progress made in directed ortho-C-H functionalization via five- or six-membered cyclopalladation, protocols with the ability to selectively activate more remote C-H bonds through the intermediacy of larger, less favorable, seven- or eight-membered metalacycles are particularly challenging and remain rare. However, such a strategy would provide new retrosynthetic opportunities for generating structural diversity and complexity. Intense recent research based on the use of either mono-anionic bidentate or monodentate directing groups is characterizing this approach as an increasingly viable tool for selective C-C and C-X bond-forming reactions. This short review provides an overview of these strategies with an emphasis on mechanistic details, synthetic applicability, limitations, and key challenges.

AbstractThe selective δ‐C(sp3)−H acetoxylation of N‐(SO2Py)‐protected amino acid derivatives has been accomplished by using palladium‐catalysis and PhI(OAc)2 (PIDA) as both terminal oxidant and acetoxy source. The distinct structural and electronic features of the SO2Py compared to more traditional carbonyl‐based directing groups is essential to override the otherwise more favourable competitive intramolecular C−H amination. The δ‐site selectivity predominates over traditionally more favorable 5‐membered cyclopalladation at competitive γ‐CH2. Experimental and DFT mechanistic studies provide important insights about the mechanism and the underlying factors controlling the chemo‐ and regioselectivity.

The exceptional versatility of sulfones has been extensively exploited in organic synthesis across several decades. Since the first demonstration in 2005 that sulfones can participate in Pd-catalysed Suzuki-Miyaura type reactions, tremendous advances in catalytic desulfitative functionalizations have opened a new area of research with burgeoning activity in recent years. This emerging field is displaying sulfone derivatives as a new class of substrates enabling catalytic C-C and C-X bond construction. In this review, we will discuss new facets of sulfone reactivity toward further expanding the flexibility of C-S bonds, with an emphasis on key mechanistic features. The inherent challenges confronting the development of these strategies will be presented, along with the potential application of this chemistry for the synthesis of natural products. Taken together, this knowledge should stimulate impactful improvements on the use of sulfones in catalytic desulfitative C-C and C-X bond formation. A main goal of this article is to bring this technology to the mainstream catalysis practice and to serve as inspiration for new perspectives in catalytic transformations.

The cooperative action of the acetate ligand, the 2-pyridyl sulfonyl (SO2Py) directing group on the alkyne substrate, and the palladium catalyst has been shown to be crucial for controlling reactivity, regioselectivity, and stereoselectivity in the acetoxylation of unsymmetrical internal alkynes under mild reaction conditions. The corresponding alkenyl acetates were obtained in good yields with complete levels of β-regioselectivity and anti-acetoxypalladation stereocontrol. Experimental and computational analyses provide insight into the reasons behind this delicate interplay between the ligand, directing group, and the metal in the reaction mechanism. In fact, these studies unveil the multiple important roles of the acetate ligand in the coordination sphere at the Pd center: (i) it brings the acetic acid reagent into close proximity to the metal to allow the simultaneous activation of the alkyne and the acetic acid, (ii) it serves as an inner-sphere base while enhancing the nucleophilicity of the acid, and (iii) it acts as an intramolecular acid to facilitate protodemetalation and regeneration of the catalyst. Further insight into the origin of the observed regiocontrol is provided by the mapping of potential energy profiles and distortion-interaction analysis.

The stereoselective photoisomerization of olefins via Energy Transfer (EnT) sensitization bears significant potential in the context of rational design of catalytic stereodivergent methodologies. Whereas approaches for controlling the access to E- and Z-isomers depend highly on the nature of the catalyst - and therefore are not easily implemented as a general strategy - EnT catalysis has emerged in recent years as an increasingly powerful tool for olefin geometry control in a nearly perfect step-economic fashion. Moreover, this approach presents both high functional group tolerance and, most notably, has demonstrated ample multicatalytic compatibility. This feature has enabled the development of tandem stereodivergent catalytic strategies, which are the focus of this Review. 1. Introduction 1.1. Stereodivergence in Modern Synthesis 1.2. E/Z Photoisomerization of Olefins as an Opportunity for Stereodivergence 2. Stereodivergent Methods Enabled by E/Z Photoisomerization 2.1. Auto Tandem Catalysis 2.2. Multicatalytic Tandem Processes 3. Applications to Stereodivergent Synthesis 3.1. Methods Based on Olefin Geometry Control 3.2. Photoisomerization and Enantiodivergence 3.3. Divergence through Isomerization of C=N Bonds 4. Conclusions

An understanding on the factors controlling C(sp2)–H vs, C(sp3)–H selectivity in Pd-catalyzed carbonylative cyclization of γ-arylated valine derivatives has allowed to reverse the remarkable selectivity of Pd for aryl C(sp2)–H over C(sp3)–H cleavage.

Despite impressive recent momentum gained in C(sp 3 )–H activation, achieving high regioselectivity in molecules containing different C–H bonds with similar high energy without abusing tailored substitution remains as one of the biggest challenges.

We describe a dual strategy in Cu catalysis based on an unprecedented dynamic multiligand coordination pool that enables cooperative closed/open shell pathways. This strategy has been applied to address a restricting limitation inherent to Cu-catalyzed B2(pin)2-carboboration of alkynes: conventional methods usually fail with alkyl electrophiles other than simple primary halides due to the very low reactivity of the intermediate vinyl-Cu(I) species. The crossover strategy enabled by ligand exchange in an organometallic intermediate overcomes this reactivity issue, thus expanding the scope of carboboration to unactivated secondary alkyl halides and opening new avenues to access of stereodefined tetrasubstituted vinylboronates. The method is regio- and stereoselective, shows excellent functional group tolerance, and allows the incorporation of complex carbo- and heterocyclic fragments at either reaction partner.

Catalytic functionalization of alkynes with organoboron reagents provides a straightforward access to stereochemically defined multisubstituted alkenes, which are structural motifs commonly found in bioactive compounds and organic materials. Recent progress has substantially broadened the scope of this field on several fronts. Strategies for regioselectivity control in the 1,2-migratory insertion across unsymmetrical internal alkynes, as well as for the direct access to products with anti-insertion stereochemistry, have been devised. The alkenyl-to-aryl 1,4-metal migration upon metal insertion has been recently exploited in powerful cascade sequences leading to complex polycyclic scaffolds, including the development of enantioselective processes. Elegant enantiospecific and dynamic kinetic resolution methods have been developed for accessing chiral allenes from propargylic alcohol derivatives. Mechanistic manifolds have emerged based on single-electron transfer (SET) that have provided a fresh impetus for alkyne 1,2-difunctionalization with complementary stereoselectivity to processes relying on 1,2-insertion of R-M species. Herein, we discuss the most recent advances in transition-metal-catalyzed functionalization of alkynes using organoboron reagents, categorized according to the type of mechanistic outcome. Emphasis is placed on mechanistic aspects, synthetic utility, limitations, and challenges for future research.

Despite the emergence of catalytic C(sp(3))-H arylation at the remote delta-position via challenging six-membered ring cyclometalation, the requirement of blocking the more reactive gamma-position represents a restricting limitation. The use of the removable N-(2-pyridyl)sulfonyl directing group provides a viable solution to this challenge, expanding the scope of the Pd-catalyzed delta-C-H arylation of a-amino acid and amine derivatives with (hetero)aryl iodides. This method is compatible with complex, multifunctional structures at either reaction partner. Experimental and density functional theory studies provide insights about the underlying factors controlling site selectivity.

A general catalytic anti-hydroarylation of electron-deficient internal alkynes compatible with both electron-poor and electron-rich aryl reagents is reported. This selectivity is achieved through a sequential syn-carbopalladation of the alkyne by an Ar-Pd species, followed by a tandem, Ir-photocatalyzed, counter-thermodynamic E → Z isomerization. The use of ortho-substituted boronic acids enables direct access to pharmaceutically relevant heterocyclic cores via a cascade process. Mechanistic insight into the involvement of Ar-Pd versus Pd-H as an active species is provided.

A general method for the construction of seven-membered rings through Pd-catalyzed C(sp(2))-H carbonylation at the remote epsilon-position of gamma-arylpropylamine derivatives, including chiral alpha-amino acids, has been developed using Mo(CO)(6) as the CO source, furnishing richly functionalized benzo[c]azepin-1-one derivatives. The readily removable N-SO2Py protecting/directing group provides high levels of chemo-, regio- and diastereoselectivity. Furthermore, this method is amenable to the postsynthetic modification of complex molecules such as small peptides.

We report on a regioselective, stereodivergent catalytic hydroarylation of unsymmetrical dialkyl alkynes with arylboronic acids that allows highly selective access to either the E or Z diastereoiso...

A new mode of reactivity of 1,3-diynes in rhodium-catalyzed oxidative annulation reactions has enabled the rapid assembly of extended π systems from readily available picolinamide derivatives. The process involves a double C-H bond activation and the iterative annulation of two 1,3-diyne units, with each alkyne moiety engaged in an orchestrated insertion sequence with high regiocontrol, leading to the formation of five new C-C bonds and the construction of four fused rings in a single operation. Either isoquinoline-1-carboxamides or fused polycyclic systems can be accessed by a switch in the regioselectivity of the second diyne insertion depending on the reaction conditions. DFT theoretical calculations have elucidated that the cooperative participation of both rhodium and copper in substrate activation, favored in the presence of excess of the copper(II) salt, is key to such a reversal of regioselectivity and subsequent multiple cyclization leading to fused polycyclic products. The role of copper was found to be essential in assisting both multiple insertion and rhodium-walking sequences, with the implication of intermediates with a Rh-Cu bond (2.60 Å).

A preliminary mechanistic approach to the Cu-catalyzed carboboration of alkynes using B-2(pin)(2) was used as a blueprint for the rational design and development of a regiocontrolled, stereoselective carboboration of internal alkynes by reaction with a beta,beta-disubstituted acrylate fragment to provide synthetically versatile and densely functionalized pyrrolidines. Experimental observations and computational analysis relevant to understanding the activation role of the alkoxide functionality in this type of carboboration process were instrumental in developing a synthetic method broad in scope and functional group tolerance. Compounds obtained by this strategy feature a stereochemically defined tetrasubstituted vinyl boronate, together with an all-carbon quaternary stereocenter. This procedure involves a tandem regioselective, chemoselective, and diastereoselective borylcupration of unsymmetrical dialkyl alkynes, followed by migratory insertion of an activated olefin to a C-Cu bond.