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.     

Nickel/Brønsted acid dual-catalyzed regio- and enantioselective hydrophosphinylation of 1,3-dienes: access to chiral allylic phosphine oxides

While chiral allylic organophosphorus compounds are widely utilized in asymmetric catalysis and for accessing bioactive molecules, their synthetic methods are still very limited. We report the development of asymmetric nickel/Brønsted acid dual-catalyzed hydrophosphinylation of 1,3-dienes with phosphine oxides. This reaction is characterized by an inexpensive chiral catalyst, broad substrate scope, and high regio- and enantioselectivity. This study allows the construction of chiral allylic phosphine oxides in a highly economic and efficient manner. Preliminary mechanistic investigations suggest that the 1,3-diene insertion into the chiral Ni–H species is a highly regioselective process and the formation of the chiral C–P bond is an irreversible step.

Asymmetric hydrophosphinylation of 1,3-dienes with phosphine oxides using an inexpensive chiral catalyst has been demonstrated, providing access to chiral allylic phosphine oxides with broad substrate scope and high regio- and enantioselectivity.     

Ligand-free nickel catalyzed perfluoroalkylation of arenes and heteroarenes

We describe a “ligand-free” Ni-catalyzed perfluoroalkylation of heteroarenes to produce a diverse array of trfiluoromethyl, pentafluoroethyl and heptafluoropropyl adducts. Catalysis proceeds at room temperature via a radical pathway. The catalytic protocol is distinguished by its simplicity, and its wide scope demonstrates the potential in the late-stage functionalization of drug analogues and peptides.

A ligand-free, room temperature, Ni-catalyzed perfluoroalkylation of heteroarenes produced a diverse array of polyfluorinated adducts; potential in the late-stage functionalization of drugs and peptides is also demonstrated.     

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.     

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.     

Catalytic defluorinative ketyl–olefin coupling by halogen-atom transfer

Ketyl–olefin coupling reactions stand as one of the fundamental chemical transformations in synthetic chemistry and have been widely employed in the generation of complex molecular architectures and natural product synthesis. However, catalytic ketyl–olefin coupling, until the recent development of photoredox chemistry and electrosynthesis through single-electron transfer mechanisms, has remained largely undeveloped. Herein, we describe a new approach to achieve catalytic ketyl–olefin coupling reactions by a halogen-atom transfer mechanism, which provides innovative and efficient access to various gem-difluorohomoallylic alcohols under mild conditions with broad substrate scope. Preliminary mechanistic experimental and computational studies demonstrate that this radical-to-polar crossover transformation could be achieved by sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and β-fluoro elimination.

A catalytic ketyl–olefin coupling reaction including sequentially orchestrated Lewis acid activation, halogen-atom transfer, radical addition, single-electron reduction and β-fluoro elimination has been developed.     

A visible-light mediated ring opening reaction of alkylidenecyclopropanes for the generation of homopropargyl radicals

Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher''s attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester activation chemistry has witnessed significant blooming developments and provided new synthetic routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis, providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives. The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile synthesis of bioactive molecules or their derivatives and medicinal substances.

A non-classical ring opening radical clock reaction using the innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis has been demonstrated, providing a brand-new synthetic approach to access a variety of alkynyl derivatives.     

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.     

Photocatalytic synthesis of tetra-substituted furans promoted by carbon dioxide

We report a simple protocol for the transition metal-free, visible-light-driven conversion of 1,3-diketones to tetra-substituted furan skeleton compounds in carbon dioxide (CO₂) atmosphere under mild conditions. It was found that CO₂ could be incorporated at the diketone enolic OH position, which was key to enabling the cleavage of a C–O bond during the rearrangement of a cyclopropane intermediate. This method allows for the same-pot construction of two isomers of the high-value tetra-substituted furan scaffold. The synthetic scope and preliminary mechanistic investigations are presented.

A CO₂-promoted transition metal-free photocatalytic synthesis of tetra-substituted furan derivatives from 1,3-diketones as the only starting material.     

Iridium-catalyzed asymmetric trans-selective hydrogenation of 1,3-disubstituted isoquinolines

The development of the first asymmetric trans-selective hydrogenation of 1,3-disubstituted isoquinolines is reported. Utilizing [Ir(cod)Cl]₂ and a commercially available chiral Josiphos ligand, a variety of differentially substituted isoquinolines are hydrogenated to produce enantioenriched trans-tetrahydroisoquinolines in good yield with high levels of enantioselectivity. Directing group studies demonstrate that the hydroxymethyl functionality at the C1 position is critical for hydrogenation to favor the trans-diastereomer. Preliminary mechanistic studies reveal that non-coordinating chlorinated solvents and halide additives are crucial to enable trans-selectivity.

trans-Selective asymmetric hydrogenation of 1,3-disubstituted isoquinolines.     

Rh(i)-catalyzed dimerization of ene-vinylidenecyclopropanes for the construction of spiro[4,5]decanes and mechanistic studies

Rh(i) complex catalyzed dimerization of ene-vinylidenecyclopropanes took place smoothly to construct a series of products containing spiro[4,5]decane skeletons featuring a simple operation procedure, mild reaction conditions, and good functional group tolerance. In this paper, the combination of experimental and computational studies reveals a counterion-assisted Rh(i)–Rh(iii)–Rh(v)–Rh(iii)–Rh(i) catalytic cycle involving tandem oxidative cyclometallation/reductive elimination/selective oxidative addition/selective reductive elimination/reductive elimination steps; in addition, a pentavalent spiro-rhodium intermediate is identified as the key intermediate in this dimerization reaction upon DFT calculation.

Rh(i) complex catalyzed dimerization of ene-vinylidenecyclopropanes has been demonstrated, and its reaction mechanism is revealed based on a series of mechanistic studies.     

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.     

Multicomponent formation route to a new class of oxygen-based 1,3-dipoles and the modular synthesis of furans

A new class of phosphorus-containing 1,3-dipoles can be generated by the multicomponent reaction of aldehydes, acid chlorides and the phosphonite PhP(catechyl). These 1,3-dipoles are formally cyclic tautomers of simple Wittig-type ylides, where the angle strain and moderate nucleophilicity in the catechyl-phosphonite favor their cyclization and also direct 1,3-dipolar cycloaddition to afford single regioisomers of substituted products. Coupling the generation of the dipoles with 1,3-dipolar cycloaddition offers a unique, modular route to furans from combinations of available aldehydes, acid chlorides and alkynes with independent control of all four substituents.

A new class of phosphorus-containing 1,3-dipoles has been developed, which, when coupled with cycloaddition, offers modular synthesis of furans with independent control of all four substituents.     

Alkylboronic acids as alkylating agents: photoredox-catalyzed alkylation reactions assisted by K3PO4

Despite the ubiquity of alkylboronic acids in organic synthesis, their utility as alkyl radical precursors in visible-light-induced photocatalytic reactions is limited by their high oxidation potentials. In this study, we demonstrated that an inorganophosphorus compound can modulate the oxidation potentials of alkylboronic acids so that they can act as alkyl radical precursors. We propose a mechanism based on the results of fluorescence quenching experiments, electrochemical experiments, ¹¹B and ³¹P NMR spectroscopy, and other techniques. In addition, we describe a simple and reliable alkylation method that has good functional group tolerance and can be used for direct C–B chlorination, cyanation, vinylation, alkynylation, and allylation, as well as late-stage functionalization of derivatized drug molecules. Notably, alkylboronic acids can be selectively activated in the presence of a boronic pinacol ester.

An alkylation method using inorganophosphorus-activated alkylboronic acids to act as alkyl radical precursors has been developed. This method can be used for direct C–B chlorination, cyanation, vinylation, alkynylation, and allylation.     

Visible-light-induced transition metal and photosensitizer free decarbonylative addition of amino-arylaldehydes to ketones

The decarbonylative-coupling reaction is generally promoted by transition metals (via organometallic complexes) or peroxides (via radical intermediates), often at high temperatures to facilitate the CO release. Herein, a visible-light-induced, transition metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes at room temperature is reported. Tertiary/secondary alcohols were obtained in moderate to excellent yields promoted by using CsF under mild conditions. The detailed mechanistic investigation showed that the reaction proceeded through photoexcitation–decarbonylation of the aldehyde to generate an aromatic anion, followed by its addition to ketones/aldehydes. The reaction mechanism was verified by the density functional theory (DFT) calculations.

A visible-light-induced, transition-metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes via anion intermediates at room temperature is developed.     

Organocopper(ii) complexes: new catalysts for carbon–carbon bond formation via electrochemical atom transfer radical addition (eATRA)

Organocopper(ii) complexes are a rarity while organocopper(i) complexes are commonplace in chemical synthesis. In the course of building a strategy to generate organocopper(ii) species utilizing electrochemistry, a method to form compounds with Cu^II–C bonds was discovered, that demonstrated remarkably potent reactivity towards different functionalized alkenes under catalytic control. The role of the organocopper(ii) complex is to act as a source of masked radicals (in this case ˙CH₂CN) that react with an alkene to generate the corresponding γ-halonitrile in good yields through atom transfer radical addition (ATRA) to various alkenes. The organocopper(ii) complexes can be continuously regenerated electrochemically for ATRA (eATRA), which proceeds at room temperature, under low Cu loadings (1–10 mol%) and with the possibility of Cu-catalyst recovery.

Electrochemical generation of a novel organocopper(ii) complex offers a new way to carry out atom transfer radical addition to alkenes under mild conditions with high yields and low catalyst loadings.     

Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives

The recent promising applications of deuterium-labeled pharmaceutical compounds have led to an urgent need for the efficient synthetic methodologies that site-specifically incorporate a deuterium atom into bioactive molecules. Nevertheless, precisely building a deuterium-containing stereogenic center, which meets the requirement for optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of chiral drug candidates, remains a significant challenge in organic synthesis. Herein, a catalytic asymmetric strategy combining H/D exchange (H/D-Ex) and azomethine ylide-involved 1,3-dipolar cycloaddition (1,3-DC) was developed for the construction of biologically important enantioenriched α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation. Directly converting glycine-derived aldimine esters into the deuterated counterparts with D₂O via Cu(i)-catalyzed H/D-Ex, and the subsequent thermodynamically/kinetically favored cleavage of the α-C–H bond rather than the α-C–D bond to generate the key N-metallated α-deuterated azomethine ylide species for the ensuing 1,3-DC are crucial to the success of α-deuterated chiral pyrrolidine synthesis. The current protocol exhibits remarkable features, such as readily available substrates, inexpensive and safe deuterium source, mild reaction conditions, and easy manipulation. Notably, the synthetic utility of a reversed 1,3-DC/[H/D-Ex] protocol has been demonstrated by catalytic asymmetric synthesis of deuterium-labelled MDM2 antagonist idasanutlin (RG7388) with high deuterium incorporation.

A strategy of combining H/D-Ex and azomethine ylide-involved 1,3-DC was developed for the construction of α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation.     

Photomediated core modification of organic photoredox catalysts in radical addition: mechanism and applications

Dihydrophenazines and their analogues have been widely used as strong reducing photoredox catalysts in radical chemistry, such as organocatalyzed atom transfer radical polymerization (O-ATRP). However, when dihydrophenazines were employed as organic photoredox catalysts (OPCs) to mediate O-ATRP, the initiator efficiency was nonquantitative due to cross-coupling between dihydrophenazines and radical species. Here, a new kind of core modification for dihydrophenazines, phenoxazines and phenothiazines was developed through this cross-coupling process. Mechanistic studies suggested that the radical species would be more likely to couple with OPC'' radical cations rather than the ground-state OPC. Core modification of OPCs could stabilize the radical ions in an oxidative quenching catalytic cycle. Significantly, core modifications of OPCs could lower the energy of light required for photoexcitation. Compared with their noncore-modified counterparts, all the core-modified dihydrophenazines and phenoxazines exhibited efficient performance in controlling O-ATRP for the synthesis of poly(methyl methacrylate) with higher initiator efficiencies under the irradiation of simulated sunlight.

Photomediated core modification of organic photocatalysts through a radical/radical cation cross-coupling process enables the ability to stabilize radical ions and prevent undesirable side reactions.     

The key role of the latent N–H group in Milstein's catalyst for ester hydrogenation

We previously demonstrated that Milstein''s seminal diethylamino-substituted PNN-pincer–ruthenium catalyst for ester hydrogenation is activated by dehydroalkylation of the pincer ligand, releasing ethane and eventually forming an NHEt-substituted derivative that we proposed is the active catalyst. In this paper, we present a computational and experimental mechanistic study supporting this hypothesis. Our DFT analysis shows that the minimum-energy pathways for hydrogen activation, ester hydrogenolysis, and aldehyde hydrogenation rely on the key involvement of the nascent N–H group. We have isolated and crystallographically characterized two catalytic intermediates, a ruthenium dihydride and a ruthenium hydridoalkoxide, the latter of which is the catalyst resting state. A detailed kinetic study shows that catalytic ester hydrogenation is first-order in ruthenium and hydrogen, shows saturation behavior in ester, and is inhibited by the product alcohol. A global fit of the kinetic data to a simplified model incorporating the hydridoalkoxide and dihydride intermediates and three kinetically relevant transition states showed excellent agreement with the results from DFT.

We report a detailed mechanistic study of ester hydrogenation catalyzed by the activated form of Milstein’s catalyst. Catalyst activation leads to the replacement of a dialkylamino side group with an NHEt group, which has a key role in catalysis.     

Visible-light-induced cross-coupling of aryl iodides with hydrazones via an EDA-complex

A visible-light-induced, transition-metal and photosensitizer-free cross-coupling of aryl iodides with hydrazones was developed. In this strategy, hydrazones were used as alternatives to organometallic reagents, in the absence of a transition metal or an external photosensitizer, making this cross-coupling mild and green. The protocol was compatible with a variety of functionalities, including methyl, methoxy, trifluoromethyl, halogen, and heteroaromatic rings. Mechanistic investigations showed that the association of the hydrazone anion with aryl halides formed an electron donor–acceptor complex, which when excited with visible light generated an aryl radical via single-electron transfer.

Visible-light-induced catalyst-free cross-coupling of aryl iodides with hydrazones via single-electron-transfer was reported. The mechanistic investigations showed that the association of hydrazone anion with aryl iodides formed an EDA complex.