Catalytic Asymmetric Redox-Neutral [3+2] Photocycloadditions of Cyclopropyl Ketones with Vinylazaarenes Enabled by Consecutive Photoinduced Electron Transfer.

Consecutive photoinduced electron transfer (ConPET) is a powerful and atom-economical protocol to overcome the limitations of the intrinsic redox potential of visible light-absorbing photosensitizers, thereby considerably improving the substrate and reaction types. Likely because such an exothermic single-electron transfer (SET) process usually does not require the aid of chiral catalysts, resulting in an inevitable racemic background reaction, notably, no enantioselective manifolds have been reported. Herein, we report on the viability of cooperative ConPET and chiral hydrogen-bonding catalysis for the [3+2] photocycloaddition of cyclopropyl ketones with vinylazaarenes. In addition to enabling the first use of olefins that preferentially interact with chiral catalysts, this catalysis platform paves the way for the efficient synthesis of pharmaceutically and synthetically important cyclopentyl ketones functionalized by azaarenes with high yields, ees and dr. The robust capacity of the method can be further highlighted by the low loading of the chiral catalyst (1.0 mol %), the good compatibility of both 2-azaarene and 3-pyridine-based olefins, and the successful concurrent construction of three stereocenters on cyclopentane rings involving an elusive but important all-carbon quaternary.

Catalytic Asymmetric Reductive Azaarylation of Olefins via Enantioselective Radical Coupling.

Visible-light-driven photocatalytic reductive azaarylation has been widely used to construct the important imine-containing azaarene derivatives. In addition to the direct use of various commercially available cyanoazaarenes as feedstocks, the synthetic advantages include precise regioselectivity, high efficiency, mild reaction conditions, and good functional group tolerance. However, although many efficient reductive azaarylation methods have been established, the example of an enantioselective manner is still unmet, which most likely can be ascribed to the highly reactive radical coupling as the key step of forming stereocenters. Exploring the feasibility of enantiocontrol thus constitutes an attractive but highly challenging task. Here, we demonstrate that chiral hydrogen-bonding/photosensitizer catalysis is a viable platform as it enables the realization of the first enantioselective manifold. A variety of acyclic and cyclic enones as the reaction partners are compatible with the dual catalyst system, leading to a wide array of valuable enantioenriched azaarene variants with high yields and ees. Regulating the types of chiral catalysts represents one of the important manners to success, in which several readily accessible Cinchona alkaloid-derived bifunctional catalysts are introduced in asymmetric photochemical reactions.

Catalytic Reductive Cross Coupling and Enantioselective Protonation of Olefins to Construct Remote Stereocenters for Azaarenes.

A novel enantioselective protonation protocol that is triggered by reductive cross coupling of olefins is reported. When under cooperative photoredox and chiral hydrogen-bonding catalytic conditions and using a terminal reductant, various α-branched vinylketones with diverse vinylazaarenes could provide important enantioenriched azaarene derivatives containing tertiary stereocenters at their remote δ-position with high yields and enantioselectivities. This reaction system is also suitable for α-branched vinylazaarenes, thus successfully assembling elusive 1,4-stereocenters. The convenient late-stage modifications of products, especially the formation of remote ε-tertiary and ε-heteroquaternary carbon stereocenters, further highlight the important synthetic value of this method. Control experiments and density functional theory (DFT) calculations were conducted to elucidate the plausible reaction mechanism and origins of regioselectivity and stereoselectivity.

All-Carbon Quaternary Stereocenters α to Azaarenes via Radical-Based Asymmetric Olefin Difunctionalization.

A radical-based asymmetric olefin difunctionalization strategy for rapidly forging all-carbon quaternary stereocenters α to diverse azaarenes is reported. Under cooperative photoredox and chiral Brønsted acid catalysis, cyclopropylamines with α-branched 2-vinylazaarenes can undergo a sequential two-step radical process, furnishing various valuable chiral azaarene-substituted cyclopentanes. The use of the rigid and confined C2-symmetric imidodiphosphoric acid catalysts achieves high enantio- and diastereo-selectivities for these asymmetric [3 + 2] cycloadditions.

Direct Enamido C(sp2 )-H Diphosphorylation Enabled by a PCET-Triggered Double Radical Relay: Access to gem-Bisphosphonates.

Herein we report a novel and straightforward protocol for the construction of valuable gem-BPs by means of proton-coupled electron-transfer (PCET)-triggered enamido C(sp2 )-H diphosphorylation. This reaction represents a rare example of realizing the challenging double C-P bond formation at a single carbon atom, thus providing facile access to a broad variety of structurally diverse bisphosphonates from simple enamides under silver-mediated conditions. Initial mechanistic studies demonstrated that the diphosphorylation involves two rounds of PCET-initiated radical relay process.

Catalytic Enantioselective Addition of Prochiral Radicals to Vinylpyridines.

Pyridine, one of the most important azaarenes, is ubiquitous in functional molecules. The electronic properties of pyridine have been exploited to trigger asymmetric transformations of prochiral species as a direct approach for accessing chiral pyridine derivatives. However, the full potential of this synthetic strategy for the construction of enantioenriched γ-functionalized pyridines remains untapped. Here, we describe the first enantioselective addition of prochiral radicals to vinylpyridines under cooperative photoredox and asymmetric catalysis mediated by visible light. The enantioselective reductive couplings of vinylpyridines with aldehydes, ketones, and imines were achieved by employing a chiral Brønsted acid to activate the reaction partners and provide stereocontrol via H-bonding interactions. Valuable chiral γ-secondary/tertiary hydroxyl- and amino-substituted pyridines were obtained in high yields with good to excellent enantioselectivities.

Conjugate Addition-Enantioselective Protonation of N-Aryl Glycines to α-Branched 2-Vinylazaarenes via Cooperative Photoredox and Asymmetric Catalysis.

An enantioselective protonation strategy has been successfully applied to the synthesis of chiral α-tertiary azaarenes. With a dual catalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer that is mediated by visible light, a variety of α-branched 2-vinylpyridines and 2-vinylquinolines with N-aryl glycines underwent a redox-neutral, radical conjugate addition-protonation process and provided valuable chiral 3-(2-pyridine/quinoline)-3-substituted amines in high yields with good to excellent enantioselectivities (up to >99% ee). An application of this methodology to a two-step synthesis of the enantiomerically pure medicinal compound pheniramine (Avil) is also presented.

Photoredox-Catalyzed Synthesis of Remote Fluoroalkylated Azaarene Derivatives and the α-Deuterated Analogues via 1,n-Hydrogen-Atom-Transfer-Involving Radical Reactions.

A modular strategy to access the remote fluoroalkylated azaarene derivatives and the α-deuterated analogues, which are the isosteres of many pharmaceutically important compounds, is reported. Transformations under the sustainable photoredox catalysis platform could efficiently experience cascade radical addition, 1,n-hydrogen atom transfer (HAT), and single-electron reduction to offer the crucial anions α to azaarenes. Through reacting with H2O or the inexpensive D2O, two series of valuable products were obtained in high yields with substantial deuterium incorporation. The work demonstrates that the HAT of the α-sp3 C-H of the electron-withdrawing azaarenes with alkyl radicals is viable.

Silver-Promoted Direct Phosphorylation of Bulky C(sp2)-H Bond to Build Fully Substituted ß-Phosphonodehydroamino Acids.

A general and practical cross-dehydrogenative coupling protocol between readily available trisubstituted α,ß-dehydro α-amino carboxylic esters and H-phosphites is described. This C(sp2)-H phosphorylation reaction proceeds with absolute Z-selectivity promoted by silver salt in a radical relay manner. The bulky tetrasubstituted ß-phosphonodehydroamino acids were obtained in grams and added new modules to the toolkit for peptide modifications.

Asymmetric aerobic decarboxylative Povarov reactions of N-aryl α-amino acids with methylenephthalimidines via cooperative photoredox and chiral Brønsted acid catalysis.

An enantioselective aerobic decarboxylative Povarov reaction of N-aryl α-amino acids with methylenephthalimidines through cooperative photoredox and chiral Brønsted acid catalysis is reported. With a transition metal-free dual catalytic system including a chiral phosphoric acid and DPZ as a photosensitizer mediated by visible light, the transformations provided a series of valuable chiral isoindolin-1-ones containing a 3,3-spiro-tetrahydroquinoline-based stereocenter in high yields (up to 83%) with good to excellent enantioselectivities (up to 98% ee) and excellent diastereoselectivity (>20 : 1 dr).

Photoredox asymmetric catalytic enantioconvergent substitution of 3-chlorooxindoles.

An enantioconvergent substitution of 3-substituted 3-chlorooxindoles with N-aryl glycines under visible light irradiation is reported. A transition-metal-free cooperative catalysis platform with a dicyanopyrazine-derived chromophore (DPZ) as a photoredox catalyst and a chiral Brønsted acid catalyst is effective for these transformations, which involve a single-electron transfer redox step and an enantioselective radical coupling. A variety of valuable chiral 3-aminomethylene-3-substituted oxindoles can be directly synthesized with high yields and enantioselectivities.

Enantioselective reduction of azaarene-based ketones via visible light-driven photoredox asymmetric catalysis.

An enantioselective reduction of azaarene-based ketones through photoredox asymmetric catalysis is reported. With a transition metal-free dual catalytic system including a chiral phosphoric acid and a photosensitizer DPZ mediated by visible light, the transformations involved a tandem process involving double single-electron-transfer reductions and enantioselective protonation, providing valuable chiral alcohols in high yields (up to >99%) with good to excellent enantioselectivities (up to 97% ee).

Enantioselective photoredox dehalogenative protonation.

We report an enantioselective photoredox dehalogenative protonation as a new type of asymmetric protonation. As a paradigm, with a cooperative catalytic system consisting of a chiral H-bonding catalyst and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer that is irradiated with visible light, a range of cyclic and acyclic ketones with labile chiral secondary C-F, C-Cl and C-Br bonds at the α-position were obtained in high yields with good to excellent enantioselectivities (up to >99% ee) by using a secondary amine as the terminal reductant. Given the ready accessibility of halides, the success of this work should provide inspiration for constructing diverse chiral α-tertiary carbonyls and their variants.

Chiral acid-catalysed enantioselective C-H functionalization of toluene and its derivatives driven by visible light.

Toluene and its derivatives are petroleum-derived raw materials produced from gasoline by catalytic reformation. These abundant chemical feedstocks are commonly used as solvents in organic synthesis. The C(sp3)-H functionalization of these unactivated substrates has been widely used to directly introduce benzylic motifs into diverse molecules to furnish important compounds. Despite these advances, progress in asymmetric catalysis remains underdeveloped. Here, we report photoinduced radical-based enantioselective C(sp3)-C(sp3) coupling reactions of activated ketones with toluene and its derivatives by means of chiral acid catalysis. With a La(OTf)3/pybox complex catalyst, a variety of chiral 3-hydroxy-3-benzyl-substituted 2-oxindoles, including many conventionally difficult-to-access variants, are obtained directly from isatins in high yields with good to excellent enantioselectivities. Acenaphthoquinone is also compatible with the use of a chiral phosphoric acid (CPA) catalyst, leading to another series of important enantioenriched tertiary alcohols.

Photoredox-Catalyzed Enantioselective α-Deuteration of Azaarenes with D2O.

The site-specific incorporation of deuterium (D) into small molecules is frequently used to access isotopically labeled compounds with broad utility in many research areas, such as drug development, mechanistic studies, and NMR analyses. Nevertheless, the deuteration of a stereocenter in an enantioselective manner, which could slow the metabolism and improve the bioavailability of bioactive molecules, remains challenging owing to the lack of established catalytic methods. Here, we report an asymmetric α-deuteration strategy for azaarenes with inexpensive D2O as the deuterium source. A cooperative visible light-driven photoredox and chiral Brønsted acid-catalyzed system using a Hantzsch ester as the terminal reductant has been developed, which enables racemic α-chloro-azaarenes and prochiral azaarene-substituted ketones to experience a single-electron reduction-enantioselective deuteration process. The transition metal-free method provides important chiral α-deuterated azaarenes in satisfactory yields with good to excellent enantioselectivities (up to 99% ee) and substantial deuterium incorporation.

Organocatalytic Enantioselective Addition of α-Aminoalkyl Radicals to Isoquinolines.

With a dual organocatalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and under the irradiation with visible light, an enantioselective Minisci-type addition of α-amino acid-derived redox-active esters (RAEs) to isoquinolines has been developed. A variety of prochiral α-aminoalkyl radicals generated from RAEs were successfully introduced on isoquinolines, providing a range of valuable α-isoquinoline-substituted chiral secondary amines in high yields with good to excellent enantioselectivities.

Catalytic enantioselective radical coupling of activated ketones with N-aryl glycines.

Asymmetric H-bonding catalysis as a viable strategy for enantioselective radical coupling of ketones is demonstrated. With a visible-light-mediated dual catalytic system involving a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and a chiral phosphoric acid (CPA), N-aryl glycines with a variety of 1,2-diketones and isatins underwent a redox-neutral radical coupling process and furnished two series of valuable chiral 1,2-amino tertiary alcohols in high yields with good to excellent enantioselectivities (up to 97% ee). In this catalysis platform, the formation of neutral radical intermediates between ketyl and H-bonding catalyst CPA is responsible for presenting stereocontrolling factors. Its success in this work should provide inspiration for expansion to other readily accessible ketones to react with various radical species, thus leading to a productive approach to access chiral tertiary alcohol derivatives.

Formal enantioconvergent substitution of alkyl halides via catalytic asymmetric photoredox radical coupling.

Classic nucleophilic substitution reactions (SN1 and SN2) are not generally amenable to the enantioselective variants that use simple and racemic alkyl halide electrophiles. The merging of transition metal catalysis and radical chemistry with organometallic nucleophiles is a versatile method for addressing this limitation. Here, we report that visible light-driven catalytic asymmetric photoredox radical coupling can act as a complementary and generic strategy for the enantioconvergent formal substitution of alkyl haldies with readily available and bench-stable organic molecules. Single-electron reductive debrominations of racemic α-bromoketones generate achiral alkyl radicals that can participate in asymmetric Csp3-Csp3 bonds forming cross-coupling reactions with α-amino radicals derived from N-aryl amino acids. A wide range of valuable enantiomerically pure ß2- and ß2,2-amino ketones were obtained in satisfactory yields with good-to-excellent enantioselectivities by using chiral phosphoric acid catalysts to control the stereochemistry and chemoselectivity. Fluoro-hetero-quaternary and full-carbon quaternary stereocenters that are challenging to prepare were successfully constructed.

Organocatalytic Asymmetric Cascade Aerobic Oxidation and Semipinacol Rearrangement Reaction: A Visible Light-Induced Approach to Access Chiral 2,2-Disubstituted Indolin-3-ones.

An enantioselective cascade aerobic oxidation and semipinacol rearrangement reaction of 2-aryl-3-alkyl-substituted indoles via visible-light-driven cooperative organophotoredox and H-bonding catalysis is reported. The current method provides an expedient and sustainable approach to furnish a variety of valuable chiral 2-aryl-2-alkyl-substituted indolin-3-ones in 64-90 % yield with 58-94 % ee. Preliminary control experiments present important insights into the stereochemistry.

Highly Regio-, Diastereo-, and Enantioselective Mannich Reaction of Allylic Ketones and Cyclic Ketimines: Access to Chiral Benzosultam.

An organocatalytic asymmetric Mannich reaction of allylic ketones with cyclic N-sulfonyl α-iminoester has been developed. By using a saccharide-derived chiral tertiary amino-thiourea catalyst, a range of allylic ketones and N-sulfonyl ketimines reacted smoothly to afford tetrasubstituted α-amino esters in high yields with good to excellent regio-, diastero-, and enantioselectivities.