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.     

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.     

Generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their synthetic applications

Organomagnesium compounds, represented by the Grignard reagents, are one of the most classical yet versatile carbanion species which have widely been utilized in synthetic chemistry. These reagents are typically prepared via oxidative addition of organic halides to magnesium metals, via halogen–magnesium exchange between halo(hetero)arenes and organomagnesium reagents or via deprotonative magnesiation of prefunctionalized (hetero)arenes. On the other hand, recent studies have demonstrated that the organo-alkaline earth metal complexes including those based on heavier alkaline earth metals such as calcium, strontium and barium could be generated from readily available non-polar unsaturated molecules such as alkenes, alkynes, 1,3-enynes and arenes through unique metallation processes. Nonetheless, the resulting organo-alkaline earth metal complexes could be further functionalized with a variety of electrophiles in various reaction modes. In particular, organocalcium, strontium and barium species have shown unprecedented reactivity in the downstream functionalization, which could not be observed in the reactivity of organomagnesium complexes. This perspective will focus on the newly emerging protocols for the generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their applications in chemical synthesis and catalysis.

In this perspective, we highlight the recent development of metallation protocols of non-polar unsaturated molecules for the generation of organo-alkaline earth metal compounds and their applications in chemical synthesis and catalysis.     

The Morita–Baylis–Hillman reaction for non-electron-deficient olefins enabled by photoredox catalysis

A strategy for overcoming the limitation of the Morita–Baylis–Hillman (MBH) reaction, which is only applicable to electron-deficient olefins, has been achieved via visible-light induced photoredox catalysis in this report. A series of non-electron-deficient olefins underwent the MBH reaction smoothly via a novel photoredox-quinuclidine dual catalysis. The in situ formed key β-quinuclidinium radical intermediates, derived from the addition of olefins with quinuclidinium radical cations, are used to enable the MBH reaction of non-electron-deficient olefins. On the basis of previous reports, a plausible mechanism is suggested. Mechanistic studies, such as radical probe experiments and density functional theory (DFT) calculations, were also conducted to support our proposed reaction pathways.

A strategy for overcoming the limitation of the Morita–Baylis–Hillman (MBH) reaction, which is only applicable to electron-deficient olefins, has been achieved via visible-light induced photoredox catalysis in this report.     

Three-component carboacylation of alkenes via cooperative nickelaphotoredox catalysis

Various commercially available acyl chlorides, aldehydes, and alkanes were exploited for versatile three-component 1,2-carboacylations of alkenes to forge two vicinal C–C bonds through the cooperative action of nickel and sodium decatungstate catalysis. A wealth of ketones with high levels of structural complexity was rapidly obtained via direct functionalization of C(sp²)/C(sp³)–H bonds in a modular manner. Furthermore, a regioselective late-stage modification of natural products showcased the practical utility of the strategy, generally featuring high resource economy and ample substrate scope.

Various commercially available acyl chlorides, aldehydes, and alkanes were exploited for versatile three-component 1,2-carboacylations of alkenes to forge two vicinal C–C bonds through the cooperative action of nickel and sodium decatungstate catalysis.     

Formal nucleophilic pyrrolylmethylation via palladium-based auto-tandem catalysis: switchable regiodivergent synthesis and remote chirality transfer

Although nucleophilic benzylation-type reaction to introduce various aromatic systems into molecules has been widely explored, the related pyrrolylmethylation version remains to be disclosed. Reported herein is a palladium-catalysed multiple auto-tandem reaction between N-Ts propargylamines, allyl carbonates and aldimines in the presence of an acid, proceeding through sequential allylic amination, cycloisomerisation, vinylogous addition and aromatisation steps. A diversity of formal pyrrolylmethylated amine products were finally furnished efficiently. In addition, switchable regiodivergent 3-pyrrolylmethylation and 4-pyrrolylmethylation were realised by tuning catalytic conditions. Moreover, remote chirality transfer with readily available enantioenriched starting materials was well achieved with an achiral ligand, relying on diastereoselective generation of η²-Pd(0) complexes between Pd(0) and chiral 1,3-diene intermediates in the key vinylogous addition step. A few control experiments were conducted to elucidate the palladium-involved tandem reaction and regiodivergent synthesis.

A formal nucleophilic pyrrolylmethylation reaction was disclosed via a palladium-catalysed tandem reaction between propargyl amines, allyl carbonates and aldimines. Switchable regiodivergent synthesis and chirality transfer could be well achieved.     

Allylic C(sp3)–H alkylation via synergistic organo- and photoredox catalyzed radical addition to imines

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described. The transformation achieves an efficient, redox-neutral synthesis of homoallylamines with broad functional group tolerance, under very mild reaction conditions. Mechanistic investigations indicate that the reaction proceeds through the N-centered radical intermediate which is generated by the allylic radical addition to the imine.

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described.     

Asymmetric β-arylation of cyclopropanols enabled by photoredox and nickel dual catalysis

The enantioselective functionalization and transformation of readily available cyclopropyl compounds are synthetically appealing yet challenging topics in organic synthesis. Here we report an asymmetric β-arylation of cyclopropanols with aryl bromides enabled by photoredox and nickel dual catalysis. This dual catalytic transformation features a broad substrate scope and good functional group tolerance at room temperature, providing facile access to a wide array of enantioenriched β-aryl ketones bearing a primary alcohol moiety in good yields with satisfactory enantioselectivities (39 examples, up to 83% yield and 90% ee). The synthetic value of this protocol was illustrated by the concise asymmetric construction of natural product calyxolane B analogues.

An asymmetric β-arylation of cyclopropanols with aryl bromides was enabled by enantioselective photoredox and nickel dual catalysis.     

Alkoxysulfonyl radical species: acquisition and transformation towards sulfonate esters through electrochemistry

Sulfonyl radical mediated processes have been considered as a powerful strategy for the construction of sulfonyl compounds. However, an efficient and high atom-economical radical approach to the synthesis of sulfonate esters is still rare, owing to the limited tactics to achieve alkoxysulfonyl radicals. Herein, an electrochemical anodic oxidation of inorganic sulfites with alcohols is developed to afford alkoxysulfonyl radical species, which are utilized in subsequent alkene difunctionalization to provide various sulfonate esters. This transformation features excellent chemoselectivity and broad functional group tolerance. This new discovery presents the potential prospect for the construction of sulfonate esters, and enriches the electrochemical reaction type.

A new route to provide alkoxysulfonyl radical species via electrochemical anodic oxidation of inorganic sulfites with alcohols is developed, affording sulfonate esters by subsequent alkene difunctionalization with these alkoxysulfonyl radicals.     

A highly selective decarboxylative deuteration of carboxylic acids

In this paper, we report a mild and practical method for precise deuteration of aliphatic carboxylic acids by synergistic photoredox and HAT catalysis. The reaction delivers excellent D-incorporation (up to 99%) at predicted sites even in substrates bearing reactive C–H bonds or versatile functional groups. The use of a recirculation reactor with a peristaltic pump supports a scalable preparative ability (up to 50 mmol) under very mild reaction conditions. The practical and precise deuteration of readily available complex carboxylic acids makes this protocol promising for the preparation of deuterium-labelled compounds.

A scalable, practical and general method for precise deuteration of aliphatic carboxylic acids via synergistic photoredox and HAT catalysis has been developed. The use of recirculation reactor achieved the preparative scale deuteration.     

Recent developments in nickel-catalyzed intermolecular dicarbofunctionalization of alkenes

Nickel-catalyzed three-component alkene difunctionalization has rapidly emerged as a powerful tool for forging two C–C bonds in a single reaction. Building upon the powerful modes of bond construction in traditional two-component cross-coupling, various research groups have demonstrated the versatility of nickel in enabling catalytic 1,2-dicarbofunctionalization using a wide range of carbon-based electrophiles and nucleophiles and in a fully intermolecular fashion. Though this area has emerged only recently, the last few years have witnessed a proliferation of publications on this topic, underscoring the potential of this strategy to develop into a general platform that offers high regio- and stereoselectivity. This minireview highlights the recent progress in the area of intermolecular 1,2-dicarbofunctionalization of alkenes via nickel catalysis and discusses lingering challenges within this reactivity paradigm.

Nickel-catalyzed three-component alkene difunctionalization has rapidly emerged as a powerful tool for forging multiple C–C bonds in a single step.     

Catalyst-free arylation of sulfonamides via visible light-mediated deamination

A novel arylation of sulfonamides with boronic acids to afford numerous diaryl sulfones via a visible light-mediated N–S bond cleavage other than the typical transition-metal-catalyzed C(O)–N bond activation is described. This methodology, which represents the first catalyst-free protocol for the sulfonylation of boronic acids, is characterized by its simple reaction conditions, good functional group tolerance and high efficiency. Several successful examples for the late-stage functionalization of diverse sulfonamides indicate the high potential utility of this method in pharmaceutical science and organic synthesis.

The simple, catalyst-free sulfonylation of boronic acids with sulfonamides via a visible light-mediated N–S bond cleavage is described, affording diaryl sulfones with high efficiency. Late-stage functionalization of sulfonamide drugs was shown.     

Stereoselective rhodium-catalyzed 2-C–H 1,3-dienylation of indoles: dual functions of the directing group

A rhodium-catalyzed intermolecular highly stereoselective 1,3-dienylation at the 2-position of indoles with non-terminal allenyl carbonates has been developed by using 2-pyrimidinyl or pyridinyl as the directing group. The reaction tolerates many functional groups affording the products in decent yields under mild conditions. In addition to C–H bond activation, the directing group also played a vital role in the determination of Z-stereoselectivity for the C–H functionalization reaction with 4-aryl-2,3-allenyl carbonates, which is confirmed by the E-selectivity observed with 4-alkyl-2,3-allenyl carbonates. DFT calculations have been conducted to reveal that π–π stacking involving the directing 2-pyrimidinyl or pyridinyl group is the origin of the observed stereoselectivity. Various synthetic transformations have also been demonstrated.

A rhodium-catalyzed intermolecular highly stereoselective 1,3-dienylation at the 2-position of indoles with non-terminal allenyl carbonates has been developed by using 2-pyrimidinyl or pyridinyl as the directing group.     

Chirality memory of α-methylene-π-allyl iridium species

Chirality is one of the most important types of steric information in nature. In addition to central chirality, axial chirality has been catching more and more attention from scientists. However, although much attention has recently been paid to the creation of axial chirality and the chirality transfer of allenes, no study has been disclosed as to the memory of such an axial chirality. The reason is very obvious: the chiral information is stored over three carbon atoms. Here, the first example of the memory of chirality (MOC) of allenes has been recorded, which was realized via an optically active alkylidene-π-allyl iridium intermediate, leading to a highly stereoselective electrophilic allenylation with amines. Specifically, we have established the transition metal-mediated highly stereoselective 2,3-allenylation of amines by using optically active 2,3-allenyl carbonates under the catalysis of a nonchiral iridium(iii) complex. This method is compatible with sterically bulky and small substituents on both amines and 2,3-allenyl carbonates and furnishes the desired optically active products with a high efficiency of chirality transfer. Further mechanistic experiments reveal that the isomerization of the optically active alkylidene-π-allyl iridium intermediate is very slow.

Chirality is one of the most important types of steric information in nature.     

Mechanistic dichotomy in the solvent dependent access to E vs. Z-allylic amines via decarboxylative vinylation of amino acids

The solvent plays an important role in the photophysical properties of donor–acceptor based photocatalysts. The solvent-dependent access to E vs. Z-allylic amines was achieved via decarboxylative vinylation of amino acids with vinyl sulfones. Detailed experimental studies have been conducted to understand the role of the solvent in the reactivity and stereoselectivity of the vinylation reactions.

A solvent-dependent access to E vs. Z-allylic amines was achieved via decarboxylative vinylation of amino acids. Detailed experimental studies have been conducted to understand the role of the solvent in the reactivity and stereoselectivity of the vinylation reactions.     

Photoredox catalysis on unactivated substrates with strongly reducing iridium photosensitizers

Photoredox catalysis has emerged as a powerful strategy in synthetic organic chemistry, but substrates that are difficult to reduce either require complex reaction conditions or are not amenable at all to photoredox transformations. In this work, we show that strong bis-cyclometalated iridium photoreductants with electron-rich β-diketiminate (NacNac) ancillary ligands enable high-yielding photoredox transformations of challenging substrates with very simple reaction conditions that require only a single sacrificial reagent. Using blue or green visible-light activation we demonstrate a variety of reactions, which include hydrodehalogenation, cyclization, intramolecular radical addition, and prenylation via radical-mediated pathways, with optimized conditions that only require the photocatalyst and a sacrificial reductant/hydrogen atom donor. Many of these reactions involve organobromide and organochloride substrates which in the past have had limited utility in photoredox catalysis. This work paves the way for the continued expansion of the substrate scope in photoredox catalysis.

Strong bis-cyclometalated iridium photoreductants, in combination with a single sacrificial reductant, enable visible-light-promoted reductive activation of a variety of challenging substrates under simple and general reaction conditions.     

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.     

Catalytic intramolecular aminoarylation of unactivated alkenes with aryl sulfonamides

Arylethylamines are abundant motifs in myriad natural products and pharmaceuticals, so efficient methods to synthesize them are valuable in drug discovery. In this work, we disclose an intramolecular alkene aminoarylation cascade that exploits the electrophilicity of a nitrogen-centered radical to form a C–N bond, then repurposes the nitrogen atom''s sulfonyl activating group as a traceless linker to form a subsequent C–C bond. This photoredox catalysis protocol enables the preparation of densely substituted arylethylamines from commercially abundant aryl sulfonamides and unactivated alkenes under mild conditions. Reaction optimization, scope, mechanism, and synthetic applications are discussed.

A photochemical assembly of cyclic arylethylamines occurs by cascade radical annulation and desulfonylative rearrangement in N-acyl sulfonamides. This aminoarylation is made possible through judicious design intended to thwart undesired reactivity.     

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.     

Photoinduced C(sp3)–H sulfination empowers the direct and chemoselective introduction of the sulfonyl group

Direct installation of the sulfinate group by the functionalization of unreactive aliphatic C–H bonds can provide access to most classes of organosulfur compounds, because of the central position of sulfinates as sulfonyl group linchpins. Despite the importance of the sulfonyl group in synthesis, medicine, and materials science, a direct C(sp³)–H sulfination reaction that can convert abundant aliphatic C–H bonds to sulfinates has remained elusive, due to the reactivity of sulfinates that are incompatible with typical oxidation-driven C–H functionalization approaches. We report herein a photoinduced C(sp³)–H sulfination reaction that is mediated by sodium metabisulfite and enables access to a variety of sulfinates. The reaction proceeds with high chemoselectivity and moderate to good regioselectivity, affording only monosulfination products and can be used for a solvent-controlled regiodivergent distal C(sp³)–H functionalization.

The photoinduced C–H sulfination of abundant aliphatic C–H bonds provides direct access to all major classes of organosulfur compounds via the intermediacy of synthetically versatile sulfinate salts.