Radical-mediated vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes

The addition of sulfonyl radicals to alkenes and alkynes is a valuable method for constructing useful highly functionalized sulfonyl compounds. The underexplored alkoxy- and fluorosulfonyl radicals are easily accessed by CF₃ radical addition to readily available allylsulfonic acid derivatives and then β-fragmentation. These substituted sulfonyl radicals add to aryl alkyl alkynes to give vinyl radicals that are trapped by trifluoromethyl transfer to provide tetra-substituted alkenes bearing the privileged alkoxy- or fluorosulfonyl group on one carbon and a trifluoromethyl group on the other. This process exhibits broad functional group compatibility and allows for the late-stage functionalization of drug molecules, demonstrating its potential in drug discovery and chemical biology.

An unprecedented method for vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes has been developed to afford useful alkenylsulfonate esters and alkenylsulfonyl fluorides.     

Copper-catalyzed hydroformylation and hydroxymethylation of styrenes

Hydroformylation catalyzed by transition metals is one of the most important homogeneously catalyzed reactions in industrial organic chemistry. Millions of tons of aldehydes and related chemicals are produced by this transformation annually. However, most of the applied procedures use rhodium catalysts. In the procedure described here, a copper-catalyzed hydroformylation of alkenes has been realized. Remarkably, by using a different copper precursor, the aldehydes obtained can be further hydrogenated to give the corresponding alcohols under the same conditions, formally named as hydroxymethylation of alkenes. Under pressure of syngas, various aldehydes and alcohols can be produced from alkenes with copper as the only catalyst, in excellent regioselectivity. Additionally, an all-carbon quaternary center containing ethers and formates can be synthesized as well with the addition of unactivated alkyl halides. A possible reaction pathway is proposed based on our results.

A copper-catalyzed hydroformylation and hydroxymethylation of alkenes has been realized.     

Radical chain monoalkylation of pyridines

The monoalkylation of N-methoxypyridinium salts with alkyl radicals generated from alkenes (via hydroboration with catecholborane), alkyl iodides (via iodine atom transfer) and xanthates is reported. The reaction proceeds under neutral conditions since no acid is needed to activate the heterocycle and no external oxidant is required. A rate constant for the addition of a primary radical to N-methoxylepidinium >10⁷ M⁻¹ s⁻¹ was experimentally determined. This rate constant is more than one order of magnitude larger than the one measured for the addition of primary alkyl radicals to protonated lepidine demonstrating the remarkable reactivity of methoxypyridinium salts towards radicals. The reaction has been used for the preparation of unique pyridinylated terpenoids and was extended to a three-component carbopyridinylation of electron-rich alkenes including enol esters, enol ethers and enamides.

N-Methoxypyridinium salts are exceptionally reactive radical traps that can be used in efficient radical chain reactions with organoboranes.     

A host–guest strategy for converting the photodynamic agents from a singlet oxygen generator to a superoxide radical generator

Type-I photosensitizers (PSs) generate cytotoxic oxygen radicals by electron transfer even in a hypoxic environment. Nevertheless, the preparation of type-I PSs remains a challenge due to the competition of triplet–triplet energy transfer with O₂ (type-II process). In this work, we report an effective strategy for converting the conventional type-II PS to a type-I PS by host–guest complexation. Electron-rich pillar[5]arenes are used as an electron donor and macrocyclic host to produce a host–guest complex with the traditional electron-deficient type-II PS, an iodide BODIPY-based guest. The host–guest complexation promotes intermolecular electron transfer from the pillar[5]arene moiety to BODIPY and then to O₂ by the type-I process upon light-irradiation, leading to efficient generation of the superoxide radical (O₂⁻˙). The results of anti-tumor studies indicate that this supramolecular PS demonstrates high photodynamic therapy efficacy even under hypoxic conditions. This work provides an efficient method to prepare type-I PSs from existing type-II PSs by using a supramolecular strategy.

A supramolecular strategy is reported for converting the conventional photodynamic agents from a singlet oxygen generator to a superoxide radical generator by the host–guest interaction enhanced electron transfer.     

Suzuki-type cross-coupling of alkyl trifluoroborates with acid fluoride enabled by NHC/photoredox dual catalysis

The Suzuki–Miyaura cross-coupling of C(sp³)-hybridised boronic compounds still remains a challenging task, thereby hindering the broad application of alkyl boron substrates in carbon–carbon bond-forming reactions. Herein, we developed an NHC/photoredox dual catalytic cross-coupling of alkyl trifluoroborates with acid fluorides, providing an alternative solution to the classical acylative Suzuki coupling chemistry. With this protocol, various ketones could be rapidly synthesised from readily available materials under mild conditions. Preliminary mechanistic studies shed light on the unique radical reaction mechanism.

An acylative Suzuki-type cross-coupling of alkyl trifluoroborates and acid fluorides was developed by merging NHC organocatalysis with photoredox catalysis. A broad spectrum of ketones could be facilely synthesised under mild reaction conditions.     

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.     

DFT insight into asymmetric alkyl–alkyl bond formation via nickel-catalysed enantioconvergent reductive coupling of racemic electrophiles with olefins

A DFT study has been conducted to understand the asymmetric alkyl–alkyl bond formation through nickel-catalysed reductive coupling of racemic alkyl bromide with olefin in the presence of hydrosilane and K₃PO₄. The key findings of the study include: (i) under the reductive experimental conditions, the Ni(ii) precursor is easily activated/reduced to Ni(0) species which can serve as an active species to start a Ni(0)/Ni(ii) catalytic cycle. (ii) Alternatively, the reaction may proceed via a Ni(i)/Ni(ii)/Ni(iii) catalytic cycle starting with a Ni(i) species such as Ni(i)–Br. The generation of a Ni(i) active species via comproportionation of Ni(ii) and Ni(0) species is highly unlikely, because the necessary Ni(0) species is strongly stabilized by olefin. Alternatively, a cage effect enabled generation of a Ni(i) active catalyst from the Ni(ii) species involved in the Ni(0)/Ni(ii) cycle was proposed to be a viable mechanism. (iii) In both catalytic cycles, K₃PO₄ greatly facilitates the hydrosilane hydride transfer for reducing olefin to an alkyl coupling partner. The reduction proceeds by converting a Ni–Br bond to a Ni–H bond via hydrosilane hydride transfer to a Ni–alkyl bond via olefin insertion. On the basis of two catalytic cycles, the origins for enantioconvergence and enantioselectivity control were discussed.

The enantioconvergent alkyl–alkyl coupling involves two competitive catalytic cycles with nickel(0) and nickel(i) active catalysts, respectively. K₃PO₄ plays a crucial role to enable the hydride transfer from hydrosilane to nickel–bromine species.     

Photoredox-catalyzed aminofluorosulfonylation of unactivated olefins

The development of efficient approaches to access sulfonyl fluorides is of great significance because of the widespread applications of these structural motifs in many areas, among which the emerging sulfur(vi) fluoride exchange (SuFEx) click chemistry is the most prominent. Here, we report the first three-component aminofluorosulfonylation of unactivated olefins by merging photoredox-catalyzed proton-coupled electron transfer (PCET) activation with radical relay processes. Various aliphatic sulfonyl fluorides featuring a privileged 5-membered heterocyclic core have been efficiently afforded under mild conditions with good functional group tolerance. The synthetic potential of the sulfonyl fluoride products has been examined by diverse transformations including SuFEx reactions and transition metal-catalyzed cross-coupling reactions. Mechanistic studies demonstrate that amidyl radicals, alkyl radicals and sulfonyl radicals are involved in this difunctionalization transformation.

A three-component aminofluorosulfonylation of unactivated alkenes has been developed by merging photocatalytic PCET with radical relay processes, affording various aliphatic sulfonyl fluorides featuring medicinally privileged heterocyclic scaffolds.     

(Fluoro)alkylation of alkenes promoted by photolysis of alkylzirconocenes

Difluoroalkylated compounds have important applications in pharmaceutical, agrochemical, and materials science. However, efficient methods to construct the alkylCF₂–alkyl bond are very limited, and the site-selective introduction of a difluoromethylene (CF₂) group into an aliphatic chain at the desired position remains challenging. Here, we report an unprecedented example of alkylzirconocene promoted difluoroalkylation of alkyl- and silyl-alkenes with a variety of unactivated difluoroalkyl iodides and bromides under the irradiation of visible light without a catalyst. The resulting difluoroalkylated compounds can serve as versatile synthons in organic synthesis. The reaction can also be applied to activated difluoroalkyl, trifluoromethyl, perfluoroalkyl, monofluoroalkyl, and nonfluorinated alkyl halides, providing a general method to controllably access fluorinated compounds. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway induced by a Zr(iii) species is involved in the reaction, in which the Zr(iii) species is generated by the photolysis of alkylzirconocene with blue light.

An unprecedented example of alkylzirconocene promoted difluoroalkylation of alkyl- and silyl-alkenes with a variety of fluoroalkyl and nonfluoroalkyl halides under the irradiation of visible light has been reported.     

General electrochemical Minisci alkylation of N-heteroarenes with alkyl halides

Herein, we report, a general, facile and environmentally friendly Minisci-type alkylation of N-heteroarenes under simple and straightforward electrochemical conditions using widely available alkyl halides as radical precursors. Primary, secondary and tertiary alkyl radicals have been shown to be efficiently generated and coupled with a large variety of N-heteroarenes. The method presents a very high functional group tolerance, including various heterocyclic-based natural products, which highlights the robustness of the methodology. This applicability has been further proved in the synthesis of various interesting biologically valuable building blocks. In addition, we have proposed a mechanism based on different proofs and pieces of electrochemical evidence.

Herein, we report, a general, facile and environmentally friendly Minisci-type alkylation of N-heteroarenes under simple and straightforward electrochemical conditions using widely available alkyl halides as radical precursors.     

Desymmetrization of pibrentasvir for efficient prodrug synthesis

A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C₂-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.

Horeau principle statistical amplification and solubility-driven selectivities allow C₂-desymmetrization of pibrentasvir without typically required internal functionalization or steric proximity effects.     

α-Branched amines through radical coupling with 2-azaallyl anions,redox active esters and alkenes

α-Branched amines are fundamental building blocks in a variety of natural products and pharmaceuticals. Herein is reported a unique cascade reaction that enables the preparation of α-branched amines bearing aryl or alkyl groups at the β- or γ-positions. The cascade is initiated by reduction of redox active esters to alkyl radicals. The resulting alkyl radicals are trapped by styrene derivatives, leading to benzylic radicals. The persistent 2-azaallyl radicals and benzylic radicals are proposed to undergo a radical–radical coupling leading to functionalized amine products. Evidence is provided that the role of the nickel catalyst is to promote formation of the alkyl radical from the redox active ester and not promote the C–C bond formation. The synthetic method introduced herein tolerates a variety of imines and redox active esters, allowing for efficient construction of amine building blocks.

A mild method for the construction of α-branched amine derivatives is presented. SET processes between the Ni catalyst, redox active esters and 2-azaallyl anions generate azaallyl radicals and alkyl radicals that functionalize the alkenes.     

NHC and visible light-mediated photoredox co-catalyzed 1,4-sulfonylacylation of 1,3-enynes for tetrasubstituted allenyl ketones

The modulation of selectivity of highly reactive carbon radical cross-coupling for the construction of C–C bonds represents a challenging task in organic chemistry. N-Heterocyclic carbene (NHC) catalyzed radical transformations have opened a new avenue for acyl radical cross-coupling chemistry. With this method, highly selective cross-coupling of an acyl radical with an alkyl radical for efficient construction of C–C bonds was successfully realized. However, the cross-coupling reaction of acyl radicals with vinyl radicals has been much less investigated. We herein describe NHC and visible light-mediated photoredox co-catalyzed radical 1,4-sulfonylacylation of 1,3-enynes, providing structurally diversified valuable tetrasubstituted allenyl ketones. Mechanistic studies indicated that ketyl radicals are formed from aroyl fluorides via the oxidative quenching of the photocatalyst excited state, allenyl radicals are generated from chemo-specific sulfonyl radical addition to the 1,3-enynes, and finally, the key allenyl and ketyl radical cross-coupling provides tetrasubstituted allenyl ketones.

Unprecedented NHC and photocatalysis co-catalyzed radical 1,4-sulfonylacylation of 1,3-enynes has been realized, providing structurally diversified tetrasubstituted allenyl ketones via allenyl and ketyl radical cross-coupling.     

Radical boron migration of allylboronic esters

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The boron atom migration through the allylic carbon skeleton proceeds via consecutive 1,2-boron migrations and Smiles-type rearrangement to furnish a variety of terminally functionalized alkyl boronates. Several types of migrating variations of heteronuclei radicals and dearomatization processes are also tolerated, allowing for further elaboration of highly functionalized boron-containing frameworks.

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The atom-switch acrobatics proceeds via cascade 1,2-boron migrations and Smiles type rearrangement to furnish a variety of terminally functionalized alkyl boronates.     

Photoinduced 1,2-dicarbofunctionalization of alkenes with organotrifluoroborate nucleophiles via radical/polar crossover

Alkene 1,2-dicarbofunctionalizations are highly sought-after transformations as they enable a rapid increase of molecular complexity in one synthetic step. Traditionally, these conjunctive couplings proceed through the intermediacy of alkylmetal species susceptible to deleterious pathways including β-hydride elimination and protodemetalation. Herein, an intermolecular 1,2-dicarbofunctionalization using alkyl N-(acyloxy)phthalimide redox-active esters as radical progenitors and organotrifluoroborates as carbon-centered nucleophiles is reported. This redox-neutral, multicomponent reaction is postulated to proceed through photochemical radical/polar crossover to afford a key carbocation species that undergoes subsequent trapping with organoboron nucleophiles to accomplish the carboallylation, carboalkenylation, carboalkynylation, and carboarylation of alkenes with regio- and chemoselective control. The mechanistic intricacies of this difunctionalization were elucidated through Stern–Volmer quenching studies, photochemical quantum yield measurements, and trapping experiments of radical and ionic intermediates.

Alkene 1,2-dicarbofunctionalizations increase molecular complexity. Herein, the carboallylation, carboalkenylation, carboalkynylation, and carboarylation of olefins is accomplished through radical/polar crossover with organotrifluoroborates.     

Stereoselective β-mannosylations and β-rhamnosylations from glycosyl hemiacetals mediated by lithium iodide

Stereoselective β-mannosylation is one of the most challenging problems in the synthesis of oligosaccharides. Herein, a highly selective synthesis of β-mannosides and β-rhamnosides from glycosyl hemi-acetals is reported, following a one-pot chlorination, iodination, glycosylation sequence employing cheap oxalyl chloride, phosphine oxide and LiI. The present protocol works excellently with a wide range of glycosyl acceptors and with armed glycosyl donors. The method doesn''t require conformationally restricted donors or directing groups; it is proposed that the high β-selectivities observed are achieved via an S_N2-type reaction of α-glycosyl iodide promoted by lithium iodide.

Breaking from the current paradigm, a highly selective synthesis of hard-to-make β-mannosides and β-rhamnosides from simple glycosyl hemi-acetals has been achieved without using conformational restrictions.     

Decarboxylative 1,4-carbocyanation of 1,3-enynes to access tetra-substituted allenes via copper/photoredox dual catalysis

We disclose herein the first example of merging photoredox catalysis and copper catalysis for radical 1,4-carbocyanations of 1,3-enynes. Alkyl N-hydroxyphthalimide esters are utilized as radical precursors, and the reported mild and redox-neutral protocol has broad substrate scope and remarkable functional group tolerance. This strategy allows for the synthesis of diverse multi-substituted allenes with high chemo- and regio-selectivities, also permitting late stage allenylation of natural products and drug molecules.

An efficient synthesis of multi-substituted allenes by metallaphotoredox-catalyzed decarboxylative 1,4-carbocyanation of 1,3-enynes is described.     

Polymeric frustrated Lewis pairs in CO2/cyclic ether coupling catalysis

Frustrated Lewis pairs (FLPs) are now ubiquitous as metal-free catalysts in an array of different chemical transformations. In this paper we show that this reactivity can be transferred to a polymeric system, offering advantageous opportunities at the interface between catalysis and stimuli-responsive materials. Formation of cyclic carbonates from cyclic ethers using CO₂ as a C₁ feedstock continues to be dominated by metal-based systems. When paired with a suitable nucleophile, discrete aryl or alkyl boranes have shown significant promise as metal-free Lewis acidic alternatives, although catalyst reuse remains illusive. Herein, we leverage the reactivity of FLPs in a polymeric system to promote CO₂/cyclic ether coupling catalysis that can be tuned for the desired epoxide or oxetane substrate. Moreover, these macromolecular FLPs can be reused across multiple reaction cycles, further increasing their appeal over analogous small molecule systems.

Polymeric frustrated Lewis pairs catalyse the coupling of epoxides and oxetanes with CO₂ with high selectivity under mild CO₂ pressures across multiple reaction cycles.     

Borane-catalyzed cascade Friedel–Crafts alkylation/[1,5]-hydride transfer/Mannich cyclization to afford tetrahydroquinolines

An unprecedented redox-neutral annulation reaction of tertiary anilines with electron-deficient alkynes was developed that proceeds through a cascade Friedel–Crafts alkylation/[1,5]-hydride transfer/Mannich cyclization sequence. Under B(C₆F₅)₃ catalysis, a range of functionalized 1,2,3,4-tetrahydroquinolines were facilely constructed in moderate to good yields with exclusive 3,4-anti-stereochemistry. The commercial availability of the catalyst and the high atom and step economy of the procedure, together with metal-free and external oxidant-free conditions, make this an attractive method in organic synthesis.

We report a redox-neutral annulation reaction of tertiary amines with electron-deficient alkynes under metal-free and oxidant-free conditions.     

Nickel-catalyzed reductive coupling of unactivated alkyl bromides and aliphatic aldehydes

A mild, convenient coupling of aliphatic aldehydes and unactivated alkyl bromides has been developed. The catalytic system features the use of a common Ni(ii) precatalyst and a readily available bioxazoline ligand and affords silyl-protected secondary alcohols. The reaction is operationally simple, utilizing Mn as a stoichiometric reductant, and tolerates a wide range of functional groups. The use of 1,5-hexadiene as an additive is an important reaction parameter that provides significant benefits in yield optimizations. Initial mechanistic experiments support a mechanism featuring an alpha-silyloxy Ni species that undergoes formal oxidative addition to the alkyl bromide via a reductive cross-coupling pathway.

Aliphatic aldehydes and alkyl bromides are reductively coupled using nickel catalysis. A BiOX ligand and 1,5-hexadiene paired with a silyl chloride and Mn as the terminal reductant are important features of the process.