Rare-earth catalyzed C-H activation offers a uniquely powerful platform for atom-economical ring construction, yet the mechanistic foundations of cascade processes that assemble polycyclic frameworks remain poorly understood. Herein, a computational investigation is reported to elucidate the mechanism of a scandium-catalyzed diastereoselective cascade cyclization of aromatic aldimines bearing tethered alkenes. The calculations establish a catalytic sequence involving the formation of active species, stereoselective intramolecular alkene insertion, intramolecular nucleophilic addition, and a rate-determining protonolysis step. The diastereoselectivity originates from a distortion-minimized alkene insertion transition state and a conformationally rigid postinsertion intermediate that enforces facial selectivity during the second cyclization. Moreover, the decisive influence of the tether architecture is uncovered. Short tethers enable low-strain six- or seven-membered ring formation, whereas tether elongation imposes prohibitive substrate distortion penalties that suppress reactivity. In addition, the oxygen atom in the tether plays an important role in the protonolysis step by alleviating steric congestion and providing a weak stabilizing O···H interaction, effects that are absent in amino- or all-carbon-tethers. These results highlight how tether-enabled preorganization governs reactivity and selectivity, providing valuable mechanistic insights for the development of new atom-efficient C-H activation strategies to access complex polycyclic compounds.

Although rare-earth-catalysed C-H addition to unsaturated hydrocarbons has emerged as a powerful and atom-economical strategy, the mechanistic principles governing selectivity in reactions involving conjugated dienes remain poorly understood. Here, density functional theory (DFT) calculations are employed to elucidate the mechanistic origins of divergent selectivity in rare-earth-catalysed pyridine C-H alkylation and aldimine annulation reactions with conjugated dienes. The results indicate that, despite producing formal 1,4- and 1,2-insertion products, respectively, both transformations proceed through a preferred 1,4-cis-insertion pathway to generate eta 3-allyl intermediates. Comprehensive computational analyses reveal that the divergence arises from distinct post-insertion pathways: sterically favored protonation at the terminal carbon in pyridine alkylation, versus electronically and sterically driven cyclization at the internal carbon in aldimine annulation. These results demonstrate that product selectivity is dictated primarily by the site-selective evolution of the eta 3-allyl intermediate rather than by the initial insertion event. This work establishes a unified mechanistic framework for diene-enabled rare-earth-catalysed C-H functionalization and provides theoretical insights into selectivity control through post-insertion reactivity.

Dinitrogen (N2), carbon monoxide (CO), and carbon dioxide (CO2) are all abundant and readily available chemical feedstocks. The functionalization of N2 with CO and CO2 is of considerable interest and importance, but remains a formidable challenge, owing to their high thermodynamic and kinetic stability. Here, we report an unprecedented cascade coupling of N2, CO, CO2, and alkynes within a dititanium framework. Sequential reactions of N2, CO, alkynes (R1C≡CR2), and CO2 with a dititanium tetrahydride complex at room temperature selectively afforded the corresponding four-component coupling products, [O2CN2CH2C(R2)CR1]4- (R1 = H, R2 = Ph, Cy, or COOMe; R1 = R2 = Me). Combined experimental and computational studies reveal that coordination of an alkyne to one Ti center of a dititanium dinitrogen/oxymethylene complex, formed via N2 and CO activation, induces N-C bond formation between the dinitrogen and oxymethylene moieties with simultaneous deoxygenation, leading to the formation of diazomethane species [NNCH2]2- at the other Ti center. Subsequent CO2 incorporation at the terminal nitrogen of the diazomethane unit triggers the addition of the CH2 unit to the coordinated alkyne, thereby generating an allylhydrazinocarboxylate species as the final four-component coupling product. This work highlights the unique synergistic reactivity of multinuclear titanium complexes toward cooperative activation and incorporation of N2, CO, and CO2, offering a new strategy for the valorization of small inert molecules at the molecular level.

Copper-catalyzed asymmetric radical reactions are powerful for synthesizing chiral molecules, which typically rely on catalysts formed in situ from copper salts and chiral ligands. However, evidence pointing to the involvement of bi- or multinuclear intermediates has rendered the true active species elusive, and this difficulty has hindered rational catalyst design and limited progress toward synthetic challenges. Herein, we report a well-defined chiral binuclear copper complex as a catalyst for the asymmetric radical trifluoromethylation-azidation of acrylates. This method delivers a variety of chiral quaternary α-azide esters, thereby providing feasible access to valuable trifluoromethylated chiral α-quaternary amino acids and related peptides. Mechanistic studies suggest that one copper center serves as the catalytic site to mediate the formation of the C–N3 bond, while the second copper center participates in bridging azide coordination. Assisted by the crescent-shaped ligand, a dicopper azide structure is constructed within a chiral cavity, thus enabling excellent enantioselective control of the reaction.

Rare-earth-catalyzed annulation reactions using alkenes via C-H activation offer an atom-efficient approach to constructing cyclic compounds. However, the mechanisms underlying these reactions remain poorly understood, limiting the rational design of related catalytic systems. Recently, Hou and Cong reported an unprecedented example of rare-earth-catalyst-controlled diastereodivergent asymmetric [3 + 2] annulation of aromatic aldimines with alkenes. To elucidate the mechanisms and the origins of diastereo- and enantioselectivity, density functional theory calculations were performed. The results revealed that the styrene insertion step determines the stereoselectivity. Styrene insertion follows a similar metal-styrene interaction pattern across different catalysts. Specifically, during cis-insertion, styrene interacts strongly with the metal center, exhibiting significant ScPh interactions, whereas such interactions are absent during trans-insertion. Thus, when the catalyst is employed with a small ligand, stereoselectivity is primarily governed by electronic factors, favoring the cis-insertion mode. In contrast, for the more sterically hindered catalyst, the ScPh interactions in cis-insertion are insufficient to overcome the steric effects, leading to a preference for the trans-insertion mode, which minimizes steric hindrance. These findings offer deeper insights into the origins of catalyst-controlled diastereo- and enantioselectivity and will also contribute to the rational design of stereospecific annulation reactions in rare-earth catalysis.

The rare-earth-catalyzed C-H alkylation of heteroatom-containing substrates with alkenes has been extensively studied over the past decade. Traditionally, those substrates have been regarded primarily as reactants in these reactions. In this study, the mechanism of rare-earth-catalyzed C-H alkylation of 2-ethylpyridine with styrene was investigated by DFT calculations, revealing the often-overlooked ligand effect of pyridine substrates. Our findings demonstrate that pyridine substrates, acting as ligands, play a pivotal role in modulating site selectivity during C-H activation. These results enhance our understanding of the rare-earth catalysis mechanism and provide valuable insights into its versatile reactivity, offering a novel perspective on the dual roles (both reactant and ligand) of heteroatom-containing substrates, which are widely used in C-H functionalization reactions.

The precise C─H functionalization of quinolines is of high interest in organic synthesis and drug discovery. However, although many strategies have been developed for the regioselective C─H bond functionalization of the quinoline scaffold, the facile and selective remote C─H bond functionalization of quinolines at the geometrically and electronically disfavored C7-position has remained underdeveloped. Here, we disclose a Cu-catalyzed formal C─H arylation and alkenylation of quinolines at the C7 position with diverse iodonium triflates. The reaction features exclusive C7-selectivity, broad substrate scope, short reaction time, and simple operation. This practical protocol has also been applied in the analogous C7-H functionalization of tetrahydroquinolines and the further C7-elaboration of quinolines. Experimental studies and density functional theory (DFT) calculations revealed that the key to the success of this transformation is the unique ring-size-induced in situ removal of the N-acyl directing group, constituting a traceless directing strategy for the rapid access to a variety of C7-substituted neutral quinolines.

Understanding how carbene reactivity is modulated by both the heteroarene scaffold and activation mode is critical for advancing selective functionalization strategies. Herein, we report a comparative study revealing the divergent reactivity of benzothiazole and benzisothiazole under both photochemical and metal-catalyzed carbene transfer conditions. Under photochemical conditions, free carbenes induce a stepwise transformation of benzothiazole involving initial carbon-atom exchange followed by carbon atom insertion, affording benzothiazoline and benzothiazine derivatives. In contrast, benzisothiazole undergoes direct monocarbon atom insertion, selectively forming ring-expanded products. Notably, metal-catalyzed carbene transfer does not proceed with aromatic benzothiazole but can efficiently engage its dearomatized intermediate through carbon atom insertion, enabling access to the same ring-expanded benzothiazine scaffolds with an expanded substrate scope. Mechanistic studies, including control experiments, isotope labeling, and DFT calculations, support the proposed pathways and clarify how scaffolds govern the distinct reactivity patterns. These findings highlight the complementary reactivity profiles of free and metal-bound carbenes and establish a structure- and activation-mode-guided platform for the selective functionalization of heteroaromatic systems.

Catalytic C-H alkylation of pyridines with unactivated internal alkenes containing heteroatom functional groups is, in principle, an ideal means for the synthesis of functionalized alkylpyridines, which are important heterocyclic structural motifs in many pharmaceuticals, agrochemicals, and biologically active compounds. However, such a transformation has remained undeveloped to date, probably due to the lack of suitable catalysts. Here we report a rare-earth-catalyzed C-H alkylation of pyridines with unactivated internal alkenes that leverages a wide array of native heteroatom functional groups, including ethers, thioethers, and tertiary amines, to serve as an efficient promoter for the regioselective hydropyridylation and hydropyridylmethylation of internal alkenes. This protocol provides an atom-efficient and straightforward approach for the selective synthesis of a new family of C2-alkylated pyridines with diverse ether, thioether, and tertiary amine functional groups, featuring 100% atom efficiency, broad substrate scope, high yield, and excellent regioselectivity. Experimental and computational studies reveal that the coordination of the heteroatom (O, S, or N) in internal alkenes to the catalyst metal center is crucial for achieving the unprecedented activity and regioselectivity.

The ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs) efficiently produces diverse poly(alpha-hydroxyalkanoic acid) (PAHA) with functional groups that are difficult to achieve via lactone polymerization. Poly(mandelic acid) (PMA), synthesized from manOCA (OCA derived from mandelic acid), is a promising polymeric material because of its high glass transition (T g) and thermal decomposition temperatures (T d). However, the synthesis of highly isotactic PMA remains challenging due to the inherent tendency to undergo epimerization during polymerization. Herein, the simple bimetallic rare-earth metal amide complex [(Me3Si)2N]3La(mu-Cl)Li(THF)3 was developed as an efficient catalyst to catalyze the ROP of L-manOCA. This catalyst effectively suppressed epimerization with high activity to afford highly isotactic PMA. The remarkable activity and isomerization selectivity were attributed to the synergistic effect between the rare-earth metal and lithium atoms in [(Me3Si)2N]3La(mu-Cl)Li(THF)3, as confirmed by density functional theory (DFT) calculations. Furthermore, the catalyst enabled precise control over polymer topology (cyclic vs linear) by modulating BnOH addition and reaction temperature. This catalyst also exhibited remarkable polymerization activity toward OCA derivatives with high isotactic selectivity. These findings lay the foundation for the development of efficient catalysts for the synthesis of highly isotactic PAHA polymers from OCA monomers.

Transition metal-catalyzed reductive coupling chemistry has been recognized as a powerful tool for the synthesis of diverse organic molecules. However, despite enormous progress in this field, there is no precedent for the tandem reductive coupling of widely accessible nitriles with electrophiles that contain sigma- and pi-type (sigma/pi-type) electrophilic functional groups simultaneously. Herein, we have established a unique cobalt catalysis system, enabling the chemoselective reductive coupling/tandem cyclization reaction of aryl halides (Br, Cl, I) bearing carbonyl moiety with a variety of aryl, alkenyl, and alkyl nitriles via the carbocobaltation of nitriles that is unknown yet. The protocol allows for the modular synthesis of structurally diverse isoquinolines with wide substrate scope (>60 examples), good functionalities tolerance, and good chemoselectivity.

The direct catalytic C-H functionalization of aromatic compounds such as anisoles and thioanisoles is of great interest and significance. However, achieving precise regioselectivity remains a major challenge. In this study, we conducted comprehensive density functional theory calculations to explore the mechanisms of rare-earth-catalyzed regioselective C-H alkylation, borylation, and silylation of anisole and thioanisole. The results reveal that in cationic C-H alkylation systems, the alkene insertion step follows a substrate-assisted mechanism, in which an additional substrate molecule acts as a ligand to facilitate the transformation. In neutral C-H borylation and silylation systems, although mononuclear hydride species readily dimerize into binuclear hydride species due to thermodynamic stability, the catalytic process predominantly proceeds via a mononuclear pathway. Furthermore, the origins of regioselectivity were thoroughly elucidated. A detailed analysis of electronic and steric effects in related transition states reveals that, for anisole, regioselectivity is primarily governed by ring strain. Since α-C(sp3)-H activation involves the formation of a highly strained three-membered ring, the reaction preferentially occurs at the ortho-C(sp2)-H site, forming a less strained four-membered ring. In contrast, for thioanisole, electronic effects play a decisive role, driving C-H activation at the more negatively charged α-C(sp3) site due to stronger metal-carbon interactions.

Since its inception in 2023, the concept of "C-H bonds as the dormant species" to control chain growth has emerged as a promising, though still evolving, strategy for precision polymer synthesis. Beyond offering a simpler polymerization method, this concept is expected to promote unprecedented reaction pathways. In this study, we report the first vinylogous anionic ring-opening polymerization (ROP) of vinylidenecyclopropanes. Cooperative La(OTf)3/DBU catalysis, in conjunction with various sp3 and sp2 C-H bonds, has streamlined the synthesis of well-defined alkyne polymers, which are amenable to further chemical modifications. Control experiments and density functional theory (DFT) calculations provide insights into the origin of selectivity and the role of dormant C-H bonds in the reversible-deactivation equilibrium.

The enantioselective C-H addition of anilines to alkenes represents an ideal protocol for the synthesis of chiral aromatic amines in terms of step- and atom-economy. However, this field remains predominantly unexplored. Herein, a series of newly designed bulky chiral anilido-oxazoline ligand precursors were synthesized, and the corresponding rare-earth metal alkyl complexes were obtained successfully. The resultant scandium complexes exhibit high regioselectivity for the ortho-C-H addition of tertiary anilines to unactivated alkenes, providing a wide range of chiral alkylated anilines in high yields (up to 98% yield) with excellent enantioselectivity (up to 98% ee). Moreover, the addition products can be easily converted into biorelevant derivatives and pharmacophore-containing skeletons.

The enantioselective [3+2] annulation of readily accessible aldimines with alkynes via C−H activation is, in principle, a straightforward and atom-efficient route for synthesizing chiral 1-aminoindenes, which are important components in a wide array of natural products, bioactive molecules, and functional materials. However, such asymmetric transformation has remained undeveloped to date due to the lack of suitable chiral catalysts. Here, we report for the first time the enantioselective [3+2] annulation of aldimines with alkynes via C−H activation using chiral half-sandwich scandium catalysts. This protocol enabled the synthesis of diverse multi-substituted chiral 1-aminoindene derivatives with 100 % atom-efficiency, broad substrate scope, and high regio- and enantioselectivity. Density functional theory (DFT) analyses have revealed that a noncovalent C−H⋅⋅⋅π interaction between a tert -Bu substituent in the chiral cyclopentadienyl (Cp) ligand and the phenyl ring of an aromatic aldimine substrate played an important role in achieving a high level of enantioselectivity. This work not only offers an efficient and selective route for synthesizing a new family of chiral 1-aminoindene derivatives but also offers unprecedented insights into enantioselectivity control in chiral Cp-ligated metal catalysts.

Selective skeletal transformations of aromatic N-heterocycles are of fundamental interest and practical importance but remain a formidable challenge due to their pronounced aromatic stability. Herein we report an unprecedented denitrogenative carbon skeleton cleavage and reorganization of pyridines mediated by the trinuclear titanium polyhydride complex [(Cp'Ti)3(μ3-H)(μ-H)6] (Cp' = C5Me4SiMe3). The reactions of 2-R-, 3-R-, and 4-R-substituted pyridines (R = Me, Et, iPr, tBu, Ph) with this titanium hydride complex at 160 °C uniformly yield the denitrogenated 3-R-substituted pentadienyl complexes [(Cp'Ti)3{μ3-η1:η2:η2:η1-CHCHC(R)CHCH}(μ-H)(μ3-N)]. Isolation and characterization of key intermediates reveal that the pyridine skeleton can be fragmented into combinations of [N]3-, [CHC(R)CHCH]4-, and [CH2]2- units or [NC(R)CHCH]4- and [CHCH]2- groups depending on the sterics and positions of the R substituents. Upon heating to 160 °C, recombination of the hydrocarbon fragments leads to the thermodynamically favored [CHCHC(R)CHCH]5- framework. These transformations proceed via multiple steps involving C-H, C-C, and C-N bond cleavages as well as C-H and C-C bond re-formations. This work underscores the unique capability of multinuclear titanium hydride clusters to mediate skeletal cleavage and reorganization of aromatic N-heterocycles, offering a new strategy for heterocycle-to-hydrocarbon molecular editing.

The rare-earth metal electrophilic carbenes are extremely active and difficult to synthesize because the rare-earth metal ion has no d-electron to donate to the empty p-orbital of the electrophilic carbene to form π-backbonding. The catalysis of this kind of complex is rarely developed. Here, novel rare-earth metal chlorides [(κ3NCN-L1)RECl(THF)(μ-Cl)]2 (RE = Y(1), Dy(2), Gd(3)) (L1 = 1-(2-N-C5H10NCH2CH2)-3-(2,6-iPr2C6H3N=CH)C8H4N) in dimeric form, and (κ3NCO-L2)RECl2(THF)2 (RE = Lu(4), Yb(5), Er(6), Y(7), Dy(8), Gd(9)) (L2 = 1-CH3OCH2CH2-3-(2,6-iPr2C6H3N=CH)C8H4N) in monomeric form bearing the indol-2-yl electrophilic carbene-based nonsymmetric NCN and NCO pincer ligands, were precisely synthesized. DFT calculations and 13C{1H} NMR results provide evidence that the indol-2-yl carbon of the ligands exhibits an electrophilic carbene character. These complexes serve as precatalysts for isoprene polymerization, featuring general compatibility with any combination of the common cocatalysts ([Ph3C][B(C6F5)4], B(C6F5)3, and [PhNHMe2][B(C6F5)4]) and alkylaluminum compounds AlR3 (R = Me, Et, iBu). They also exhibit high catalytic activity in isoprene polymerization, yielding polymers with high 1,4-cis-selectivity (up to 99.6%) and ultrahigh number-average molecular weights (Mn up to 144.85 × 104 g·mol-1). Additionally, the results reveal that catalyst activity is determined by the substituents of the ligands, coordinated THF, and coordination modes of the complexes.

Catalytic multicomponent carbonylation reactions with high regio- and chemoselectivity represent one of the long-pursued goals in C1 chemistry. We herein disclose a practical cobalt-catalyzed divergent radical alkene carbonylative functionalization under 1 atm of CO at 23 °C. The leverage of the tridentate NNN-type pincer ligand is the key to avoid the formation of catalytically inert Co 0 (CO) n species and overcome the occurrence of oxidative carbonylation of organozincs, selectively tuning the catalytic reactivity of cobalt center for dictating a full cobalt-catalyzed four-component carbonylation. Moreover, direct use CO 2 as the C1 source in the multicomponent alkene carbonylative couplings can be achieved under a tandem electro-thermo-catalysis, thus allowing us to rapidly and reliably construct unsymmetric ketones with ample scope and excellent functional group compatibility. Remarkably, our protocol encompasses a broader of polyhaloalkanes as the electrophiles, which underwent radical-relay couplings in a completely regio- and chemoselective fashion. Finally, facile modifications of drug-like molecules demonstrate the synthetic utility of this method.

We present here a chiral phosphoric acid-catalyzed asymmetric Doyle indolization enabling efficient construction of axially chiral indolizinylindoles with stable C-N stereogenic axes. Importantly, this intriguing cascade cyclization realized the highly enantioselective synthesis of axially chiral o-quarteraryl skeletons containing two contiguous stereogenic axes in good to high yields and excellent stereoselectivities. Furthermore, an atropo-divergent synthesis was achieved via switching the 3,3'-substituents of the CPA catalyst. The potential synthetic utility of this method was further illustrated by easy scale-up and diverse late-stage functionalizations through reduction or oxidation.

We present herein a highly efficient atroposelective synthesis of five/five-membered N-indolizinylpyrrole through the chiral phosphoric acid (CPA) catalyzed Paal-Knorr reaction of 3-aminoindolizines and 1,4-diketones. The reaction features mild reaction conditions, broad substrate scope and excellent enantioselectivity. Moreover, this method provides a facile approach to a novel axially chiral indolizine-pyrrole framework.