Exploring benzylic gem-C(sp3)–boron–silicon and boron–tin centers as a synthetic platform

A stepwise build-up of multi-substituted C_sp³ carbon centers is an attractive, conceptually simple, but often synthetically challenging type of disconnection. To this end, this report describes how gem-α,α-dimetalloid-substituted benzylic reagents bearing boron/silicon or boron/tin substituent sets are an excellent stepping stone towards diverse substitution patterns. These gem-dimetalloids were readily accessed, either by known carbenoid insertion into C–B bonds or by the newly developed scalable deprotonation/metallation approach. Highly chemoselective transformations of either the C–Si (or C–Sn) or the C–B bonds in the newly formed gem-C_sp³ centers have been achieved through a set of approaches, with a particular focus on exploiting the synthetically versatile polarity reversal in organometalloids by λ³-aryliodanes. Of particular note is the metal-free arylation of the C–Si (or C–Sn) bonds in such gem-dimetalloids via the iodane-guided C–H coupling approach. DFT calculations show that this transfer of the (α-Bpin)benzyl group proceeds via unusual [5,5]-sigmatropic rearrangement and is driven by the high-energy iodine(iii) center. As a complementary tool, the gem-dimetalloid C–B bond is shown to undergo a potent and chemoselective Suzuki–Miyaura arylation with diverse Ar–Cl, thanks to the development of the reactive gem-α,α-silyl/BF₃K building blocks.

This work explores divergent reactivity of the benzylic gem-boron–silicon and boron–tin double nucleophiles, including the arylation of the C–B bond with Ar–Cl, along with a complementary oxidative λ³-iodane-guided arylation of the C–Si/Sn moiety.     

Modulation of the superficial electronic structure via metal–support interaction for H2 evolution over Pd catalysts

Electronic interactions can radically enhance the performance of supported metal catalysts and are critical for fundamentally understanding the nature of catalysts. However, at the microscopic level, the details of such interactions tuning the electronic properties of the sites on the metal particle''s surface and metal–support interface remain obscure. Herein, we found polarized electronic metal–support interaction (pEMSI) in oxide-supported Pd nanoparticles (NPs) describing the enhanced accumulation of electrons at the surface of NPs (superficial Pd^δ−) with positive Pd atoms distributed on the interface (interfacial Pd^δ+). More superficial Pd^δ− species mean stronger pEMSI resulting from the synergistic effect of moderate Pd–oxide interaction, high structural fluxionality and electron transport activity of Pd NPs. The surface Pd^δ− species are responsible for improved catalytic performance for H₂ evolution from metal hydrides and formates. These extensive insights into the nature of supported-metal NPs may open new avenues for regulating a metal particle''s electronic structure precisely and exploiting high-performance catalysts.

A new type of electronic effect, polarized metal-support interaction (pEMSI), in oxide-supported Pd nanoparticles describing the enhanced accumulation of electrons at the superficial surface is responsible for improved catalytic H₂ evolution.     

Ligand-controlled regioselective and chemodivergent defluorinative functionalization of gem-difluorocyclopropanes with simple ketones

Modulating the reaction selectivity is highly attractive and pivotal to the rational design of synthetic regimes. The defluorinative functionalization of gem-difluorocyclopropanes constitutes a promising route to construct β-vinyl fluorine scaffolds, whereas chemo- and regioselective access to α-substitution patterns remains a formidable challenge. Presented herein is a robust Pd/NHC ligand synergistic strategy that could enable the C–F bond functionalization with exclusive α-regioselectivity with simple ketones. The key design adopted enolates as π-conjugated ambident nucleophiles that undergo inner-sphere 3,3′-reductive elimination warranted by the sterically hindered-yet-flexible Pd-PEPPSI complex. The excellent branched mono-defluorinative alkylation was achieved with a sterically highly demanding IHept ligand, while subtly less bulky SIPr acted as a bifunctional ligand that not only facilitated α-selective C(sp³)–F cleavage, but also rendered the newly-formed C(sp²)–F bond as the linchpin for subsequent C–O bond formation. These examples represented an unprecedented ligand-controlled regioselective and chemodivergent approach to various mono-fluorinated terminal alkenes and/or furans from the same readily available starting materials.

A robust Pd/NHC ligand synergistic strategy that enables the exquisite regioselective and chemodivergent C–F bond functionalization of gem-difluorocyclopropanes with simple ketones, is reported.     

Organocatalytic strategy for hydrophenolation of gem-difluoroalkenes

Gem-difluoroalkenes are an easily accessed fluorinated functional group, and a useful intermediate for elaborating into more complex fluorinated compounds. Currently, most functionalization reactions of gem-difluoroalkenes, with or without a transition metal-based catalyst system, involve the addition or removal of a fluorine atom to generate trifluorinated or monofluorinated products, respectively. In contrast, we present a complementary “fluorine-retentive” reaction that exploits an organocatalytic strategy to add phenols across gem-difluoroalkenes to deliver β,β-difluorophenethyl arylethers. The products are produced in good to moderate yields and selectivities, thus providing a range of compounds that are underrepresented in the synthetic and medicinal chemistry literature.     

Temperature-modulated selective C(sp3)–H or C(sp2)–H arylation through palladium catalysis

Transition metal-catalysed C–H bond functionalisations have been extensively developed in organic and medicinal chemistry. Among these catalytic approaches, the selective activation of C(sp³)–H and C(sp²)–H bonds is particularly appealing for its remarkable synthetic versatility, yet it remains highly challenging. Herein, we demonstrate the first example of temperature-dependent selective C–H functionalisation of unactivated C(sp³)–H or C(sp²)–H bonds at remote positions through palladium catalysis using 7-pyridyl-pyrazolo[1,5-a]pyrimidine as a new directing group. At 120 °C, C(sp³)–H arylation was triggered by the chelation of a rare [6,5]-fused palladacycle, whereas at 140 °C, C(sp²)–H arylation proceeded instead through the formation of a 16-membered tetramer containing four 7-pyridyl-pyrazolo[1,5-a]pyrimidine–palladium chelation units. The subsequent mechanistic study revealed that both C–H activations shared a common 6-membered palladacycle intermediate, which was then directly transformed to either the [6,5]-fused palladacycle for C(sp³)–H activation at 120 °C or the tetramer for C(sp²)–H arylation at 140 °C with catalytic amounts of Pd(OAc)₂ and AcOH. Raising the temperature from 120 °C to 140 °C can also convert the [6,5]-fused palladacycle to the tetramer with the above-mentioned catalysts, hence completing the C(sp²)–H arylation ultimately.

Unprecedented 16-membered tetramer or [6,5]-fused palladacycle, mutually shadowboxing-like transformed from the shared common intermediate, accomplishes the Pd-catalysed temperature-dependent selective arylation of C(sp²)–H or C(sp³)–H.     

Recent advances in the synthesis and CF functionalization of gem-difluoroalkenes

The gem-difluoroalkenes and related compounds have gained much attention from the organic synthetic community due to their widespread applications as versatile fluorinated building blocks for the synthesis of pharmaceuticals, agrochemicals and functional materials. In the past two decades, significant progress has been made to the development of efficient methods for the construction of gem-difluoroalkenes and useful reactions involving the cleavage of CF bond in gem-difluoroalkenes. In this Digest review, these advances in the synthesis and reaction chemistry of gem-difluoroalkenes are summarized, with special emphasis placed on novel synthetic applications of them in recent ten years.     

Ti-catalyzed ring-opening oxidative amination of methylenecyclopropanes with diazenes

The ring-opening oxidative amination of methylenecyclopropanes (MCPs) with diazenes catalyzed by py₃TiCl₂(NR) complexes is reported. This reaction selectively generates branched α-methylene imines as opposed to linear α,β-unsaturated imines, which are difficult to access via other methods. Products can be isolated as the imine or hydrolyzed to the corresponding ketone in good yields. Mechanistic investigation via density functional theory suggests that the regioselectivity of these products results from a Curtin–Hammett kinetic scenario, where reversible β-carbon elimination of a spirocyclic [2 + 2] azatitanacyclobutene intermediate is followed by selectivity-determining β-hydrogen elimination of the resulting metallacycle. Further functionalizations of these branched α-methylene imine products are explored, demonstrating their utility as building blocks.

The ring-opening oxidative amination of methylenecyclopropanes (MCPs) with diazenes catalyzed by py₃TiCl₂(NR) complexes is reported.     

Walking metals: catalytic difunctionalization of alkenes at nonclassical sites

Migration of metals along a carbon chain is triggered by two of the most common organometallic elementary steps – β-hydride (β-H) elimination and alkene hydrometallation. This process heralds a new future for creating bonds at carbon sites that fall outside the tenets of the conventional wisdom for reactivity and bond formation, and provides an opportunity to leverage β-H elimination to advance the very reaction of alkene difunctionalization it is intrinsically predestined to disrupt. Almost four decades since its genesis, the early adventure for alkene difunctionalization by metal migration was sporadic, and its later development went on a hiatus primarily due to original impetus on arresting β-H elimination for vicinal alkene difunctionalization. With the recent surge on alkene difunctionalization, efforts have been gradually shifting to harnessing the process of β-H elimination to difunctionalize alkenes at sites other than the classical vicinal carbons, termed henceforth nonclassical reaction sites for pedagogical simplicity. In this review article, we extricate and examine the origin and the development of such reactions over the years. This review covers a wide range of reactions for the difunctionalization of alkenes at geminal (1,1), allylic (1,3) and remote (1,n) carbon sites with a variety of coupling partners. These reactions have enabled engineering of complex molecular frameworks with the generation of new carbon–carbon (C–C)/C–C, C–C/C–heteroatom (halogens, O, N, B) and C–B/C–B bonds. The development of these unique transformations is also presented with mechanistic hypotheses and experimental evidences put forward by researchers. Judged by the number of reports emerging recently, it is now strikingly evident that the field of alkene difunctionalization by metal migration has begun to gain momentum, which holds a great future prospect to develop into a synthetic method of enormous potential.

Alkenes can be difunctionalized at unconventional carbon sites by the migration of transition metals through β-hydride elimination and hydrometallation steps.     

Visible light driven deuteration of formyl C–H and hydridic C(sp3)–H bonds in feedstock chemicals and pharmaceutical molecules

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D₂O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp³)–H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C–H bonds of aldehydes and other activated hydridic C(sp³)–H bonds can be achieved in a selective manner.

A selective hydrogen deuterium exchange reaction with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds has been achieved by merging tetra-n-butylammonium decatungstate photocatalyst and a thiol catalyst under 390 nm light irradiation.     

Preparation of α-amino acids via Ni-catalyzed reductive vinylation and arylation of α-pivaloyloxy glycine

This work emphasizes easy access to α-vinyl and aryl amino acids via Ni-catalyzed cross-electrophile coupling of bench-stable N-carbonyl-protected α-pivaloyloxy glycine with vinyl/aryl halides and triflates. The protocol permits the synthesis of α-amino acids bearing hindered branched vinyl groups, which remains a challenge using the current methods. On the basis of experimental and DFT studies, simultaneous addition of glycine α-carbon (Gly) radicals to Ni(0) and Ar–Ni(ii) may occur, with the former being more favored where oxidative addition of a C(sp²) electrophile to the resultant Gly–Ni(i) intermediate gives a key Gly–Ni(iii)–Ar intermediate. The auxiliary chelation of the N-carbonyl oxygen to the Ni center appears to be crucial to stabilize the Gly–Ni(i) intermediate.

We have developed Ni-catalyzed reductive coupling of N-carbonyl protected α-pivaloyloxy glycine with Csp²-electrophiles that enabled facile preparation of α-amino acids, including those bearing hindered branched vinyl groups.     

Understanding the unique reactivity patterns of nickel/JoSPOphos manifold in the nickel-catalyzed enantioselective C–H cyclization of imidazoles

The 3d transition metal-catalyzed enantioselective C–H functionalization provides a sustainable strategy for the construction of chiral molecules. A better understanding of the catalytic nature of the reactions and the factors controlling the enantioselectivity is important for rational design of more efficient systems. Herein, the mechanisms of Ni-catalyzed enantioselective C–H cyclization of imidazoles are investigated by density functional theory (DFT) calculations. Both the π-allyl nickel(ii)-promoted σ-complex-assisted metathesis (σ-CAM) and the nickel(0)-catalyzed oxidative addition (OA) mechanisms are disfavored. In addition to the typically proposed ligand-to-ligand hydrogen transfer (LLHT) mechanism, the reaction can also proceed via an unconventional σ-CAM mechanism that involves hydrogen transfer from the JoSPOphos ligand to the alkene through P–H oxidative addition/migratory insertion, C(sp²)–H activation via σ-CAM, and C–C reductive elimination. Importantly, computational results based on this new mechanism can indeed reproduce the experimentally observed enantioselectivities. Further, the catalytic activity of the π-allyl nickel(ii) complex can be rationalized by the regeneration of the active nickel(0) catalyst via a stepwise hydrogen transfer, which was confirmed by experimental studies. The calculations reveal several significant roles of the secondary phosphine oxide (SPO) unit in JoSPOphos during the reaction. The improved mechanistic understanding will enable design of novel enantioselective C–H transformations.

Several unique reactivity patterns of the Ni/JoSPOphos manifold, including facile hydrogen transfer via the two-step oxidative addition/migratory insertion and C(sp²)–H activation via an unconventional σ-CAM mechanism, were disclosed in this work.     

Diverse ring-opening reactions of rhodium η4-azaborete complexes

Sequential treatment of [Rh(COE)₂Cl]₂ (COE = cyclooctene) with PⁱPr₃, alkyne derivatives and ^tBuN BMes (Mes = 2,4,6-trimethylphenyl) provided functionalized rhodium η⁴-1,2-azaborete complexes of the form (η⁴-azaborete)RhCl(PⁱPr₃). The scope of this reaction was expanded to encompass alkynes with hydrogen, alkyl, aryl, ferrocenyl, alkynyl, azaborinyl and boronate ester substituents. Treatment of these complexes with PMe₃ led to insertion of the rhodium atom into the B–C bond of the BNC₂ ring, forming 1-rhoda-3,2-azaboroles. Addition of N-heterocyclic carbenes to azaborete complexes led to highly unusual rearrangements to rhodium η²,κ¹-allenylborylamino complexes via deprotonation and C–N bond cleavage. Heating and photolysis of an azaborete complex also led to rupture of the C–N bond followed by subsequent rearrangements, yielding an η⁴-aminoborylallene complex and two isomeric η⁴-butadiene complexes.

Rhodium η⁴-azaborete complexes can be transformed into a variety of species with ring-opened, BN-containing ligands by treatment with Lewis bases.     

Direct electrochemical defluorinative carboxylation of α-CF3 alkenes with carbon dioxide

An unprecedented γ-carboxylation of α-CF₃ alkenes with CO₂ is reported. This approach constitutes a rare example of using electrochemical methods to achieve regioselectivity complementary to conventional metal catalysis. Accordingly, using platinum plate as both a working cathode and a nonsacrificial anode in a user-friendly undivided cell under constant current conditions, the γ-carboxylation provides efficient access to vinylacetic acids bearing a gem-difluoroalkene moiety from a broad range of substrates. The synthetic utility is further demonstrated by gram-scale synthesis and elaboration to several value-added products. Cyclic voltammetry and density functional theory calculations were performed to provide mechanistic insights into the reaction.

A γ-carboxylation of α-CF₃ alkenes with CO₂ using platinum plate as both working cathode and nonsacrificial anode has been developed.     

The site-selectivity and mechanism of Pd-catalyzed C(sp2)–H arylation of simple arenes

Control over site-selectivity is a critical challenge for practical application of catalytic C–H functionalization reactions in organic synthesis. Despite the seminal breakthrough of the Pd-catalyzed C(sp²)–H arylation of simple arenes via a concerted metalation–deprotonation (CMD) pathway in 2006, understanding the site-selectivity of the reaction still remains elusive. Here, we have comprehensively investigated the scope, site-selectivity, and mechanism of the Pd-catalyzed direct C–H arylation reaction of simple arenes. Counterintuitively, electron-rich arenes preferably undergo meta-arylation without the need for a specifically designed directing group, whereas electron-deficient arenes bearing fluoro or cyano groups exhibit high ortho-selectivity and electron-deficient arenes bearing bulky electron-withdrawing groups favor the meta-product. Comprehensive mechanistic investigations through a combination of kinetic measurements and stoichiometric experiments using arylpalladium complexes have revealed that the Pd-based catalytic system works via a cooperative bimetallic mechanism, not the originally proposed monometallic CMD mechanism, regardless of the presence of a strongly coordinating L-type ligand. Notably, the transmetalation step, which is influenced by a potassium cation, is suggested as the selectivity-determining step.

The transmetalation step, not the C–H activation step, is suggested as the selectivity-determining step in Pd-catalyzed C–H arylation of simple arenes.     

Photoactive electron donor–acceptor complex platform for Ni-mediated C(sp3)–C(sp2) bond formation

A dual photochemical/nickel-mediated decarboxylative strategy for the assembly of C(sp³)–C(sp²) linkages is disclosed. Under light irradiation at 390 nm, commercially available and inexpensive Hantzsch ester (HE) functions as a potent organic photoreductant to deliver catalytically active Ni(0) species through single-electron transfer (SET) manifolds. As part of its dual role, the Hantzsch ester effects a decarboxylative-based radical generation through electron donor–acceptor (EDA) complex activation. This homogeneous, net-reductive platform bypasses the need for exogenous photocatalysts, stoichiometric metal reductants, and additives. Under this cross-electrophile paradigm, the coupling of diverse C(sp³)-centered radical architectures (including primary, secondary, stabilized benzylic, α-oxy, and α-amino systems) with (hetero)aryl bromides has been accomplished. The protocol proceeds under mild reaction conditions in the presence of sensitive functional groups and pharmaceutically relevant cores.

This works demonstrates the implementation of an electron donor–acceptor (EDA) complex platform toward Ni-catalyzed C(sp³)–C(sp²) bond formation, circumventing the need for exogenous photocatalysts, additives, and stoichiometric metal reductants.     

Photo-induced copper-catalyzed alkynylation and amination of remote unactivated C(sp3)-H bonds

A method for remote radical C–H alkynylation and amination of diverse aliphatic alcohols has been developed. The reaction features a copper nucleophile complex formed in situ as a photocatalyst, which reduces the silicon-tethered aliphatic iodide to an alkyl radical to initiate 1,n-hydrogen atom transfer. Unactivated secondary and tertiary C–H bonds at β, γ, and δ positions can be functionalized in a predictable manner.

Remote C−H alkynylation and amination of aliphatic alcohols.     

Reversible metathesis of ammonia in an acyclic germylene–Ni0 complex

Carbenes, a class of low-valent group 14 ligand, have shifted the paradigm in our understanding of the effects of supporting ligands in transition-metal reactivity and catalysis. We now seek to move towards utilizing the heavier group 14 elements in effective ligand systems, which can potentially surpass carbon in their ability to operate via ‘non-innocent’ bond activation processes. Herein we describe our initial results towards the development of scalable acyclic chelating germylene ligands (viz.1a/b), and their utilization in the stabilization of Ni⁰ complexes (viz.4a/b), which can readily and reversibly undergo metathesis with ammonia with no net change of oxidation state at the Ge^II and Ni⁰ centres, through ammonia bonding at the germylene ligand as opposed to the Ni⁰ centre. The DFT-derived metathesis mechanism, which surprisingly demonstrates the need for three molecules of ammonia to achieve N–H bond activation, supports reversible ammonia binding at Ge^II, as well as the observed reversibility in the overall reaction.

Chelating single-centre ambiphile ligands based upon low-coordinate, acyclic germylenes have been developed, remaining highly Lewis acidic even when bound to Ni⁰, remarkably allowing for the reversible metathesis of the N–H bonds in ammonia at Ge^II.     

Photoredox-enabled 1,2-dialkylation of α-substituted acrylates via Ireland–Claisen rearrangement

Herein, we report the 1,2-dialkylation of simple feedstock acrylates for the synthesis of valuable tertiary carboxylic acids by merging Giese-type radical addition with an Ireland–Claisen rearrangement. Key to success is the utilization of the reductive radical-polar crossover concept under photocatalytic reaction conditions to force the [3,3]-sigmatropic rearrangement after alkyl radical addition to allyl acrylates. Using readily available alkyl boronic acids as radical progenitors, this redox-neutral, transition-metal-free protocol allows the mild formation of two C(sp³)–C(sp³) bonds, thus providing rapid access to complex tertiary carboxylic acids in a single step. Moreover, this strategy enables the efficient synthesis of highly attractive α,α-dialkylated γ-amino butyric acids (GABAs) when α-silyl amines are used as radical precursors – a structural motif that was still inaccessible in related transformations. Depending on the nature of the radical precursors and their inherent oxidation potentials, either a photoredox-induced radical chain or a solely photoredox mechanism is proposed to be operative.

A photocatalytic 1,2-dialkylation of α-substituted acrylates is enabled by a reaction cascade combining reductive radical-polar crossover with the established Ireland–Claisen rearrangement for the synthesis of valuable tertiary carboxylic acids.     

Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls

Construction of C–C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C–C bonds in a tricomponent process.

α-Branched carboxylic acids and other carbonyls are readily accessed by a metal- and base-free deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls via boron enolates, resulting in a tricomponent coupling with unconventional electrophiles.     

A step-economic and one-pot access to chiral Cα-tetrasubstituted α-amino acid derivatives via a bicyclic imidazole-catalyzed direct enantioselective C-acylation

C^α-Tetrasubstituted α-amino acids are ubiquitous and unique structural units in bioactive natural products and pharmaceutical compounds. The asymmetric synthesis of these molecules has attracted a lot of attention, but a more efficient method is still greatly desired. Here we describe the first sequential four-step acylation reaction for the efficient synthesis of chiral C^α-tetrasubstituted α-amino acid derivatives from simple N-acylated amino acids via an auto-tandem catalysis using a single nucleophilic catalyst. The synthetic efficiency is improved via a direct enantioselective C-acylation; the methodology affords the corresponding C^α-tetrasubstituted α-amino acid derivatives with excellent enantioselectivities (up to 99% ee). This step-economic, one-pot, and auto-tandem strategy provides facile access to important chiral building blocks, such as peptides, serines, and oxazolines, which are often used in medicinal and synthetic chemistry.

The first four-step sequential reaction for the synthesis of C^α-tetrasubstituted chiral α-amino acid derivatives via auto-tandem catalysis has been developed.