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We demonstrate hydrohalogenation of aliphatic alkenes with collidine·HX salts through dual photoredox/cobalt catalysis. The dual catalysis enables conversion of a proton and a halide anion from collidine·HX salt to a nucleophilic hydrogen radical equivalent and an electrophilic halogen radical equivalent and delivery of them to an alkene moiety. This protocol allows for introduction of fluorine, chlorine, bromine, or iodine atom to alkene, producing highly functionalized alkyl halides.

4′-Selective alkylation of nucleosides has been recognized as one of the ideal and straightforward approaches to chemically modified nucleosides, but such a transformation has been scarce and less explored. In this Letter, we combine a visible-light-mediated photoredox catalysis and hydrogen atom transfer (HAT) auxiliary to achieve β-C(sp3)–H alkylation of alcohol on tetrahydrofurfuryl alcohol scaffolds and exploit it for 4′-selective alkylation of nucleosides. The reaction involves an intramolecular 1,5-HAT process and stereocontrolled Giese addition of the resultant radicals.

A radical-mediated cyclopropanation tool for reactive alkenes including dehydroamino acids (DHAAs) has been developed based on directly photoexcitable borate generating iodomethyl radical under visible light irradiation. The borate at the excited state serves as a strong single electron reductant. Therefore, this photoexcitable borate offers a simple protocol for cyclopropanation of DHAAs to forge medicinally-important cyclopropane amino acids.A radical-mediated cyclopropanation tool for reactive alkenes including dehydroamino acids (DHAAs) has been developed based on directly photoexcitable borate generating iodomethyl radical under visible light irradiation. The borate at the excited state serves as a strong single electron reductant. Therefore, this photoexcitable borate offers a simple protocol for cyclopropanation of DHAAs to forge medicinally-important cyclopropane amino acids.

We demonstrate Markovnikov hydroalkoxylation of unactivated alkenes using alcohols through a triple catalysis consisting of photoredox, cobalt, and Brønsted acid catalysts under visible light irradiation. The triple catalysis realizes three key elementary steps in a single catalytic cycle: (1) Co(III) hydride generation by photochemical reduction of Co(II) followed by protonation, (2) metal hydride hydrogen atom transfer (MHAT) of alkenes by Co(III) hydride, and (3) oxidation of the alkyl Co(III) complex to alkyl Co(IV). The precise control of protons and electrons by the three catalysts allows the elimination of strong acids and external reductants/oxidants that are required in the conventional methods.

A molecular-field-based regression analysis using computational screening data for N-heterocyclic carbene (NHC)-Cu-catalyzed asymmetric carbonyl additions of a silylboronate to aldehydes is reported. A computational screening was performed to collect enantioselectivity data (ΔΔG‡: energy differences between the transition states leading to each enantiomer) via transition-state (TS) calculations using density functional theory (DFT) methods. A molecular field analysis (MFA) was carried out using the obtained calculated ΔΔG‡values and TS structures (30 samples in total). Important structural information for enantioselectivity extracted by the MFA was visualized on the TS structures, which provided insight into an asymmetric induction mechanism. Based on the obtained information, chiral NHC ligands were designed, which showed improved enantioselectivity in these carbonyl additions (designed ligands: up to 96% ee, initial training samples: up to 73% ee).A molecular field analysis using computational-screening data and the corresponding transition-state structures with a relatively small dataset (30 samples) enabled the regression-based data-driven design of chiral NHC ligands with improved enantioselectivity for the Cu-catalyzed carbonyl addition of a silylboronate.

This manuscript represents an organophotoredox-catalyzed decarboxylative fluorination of alkyl redox active esters with triethylamine trihydrofluoride. The reaction proceeds through a radical-polar crossover mechanism to generate a carbocation equivalent under non-acidic and transition metal free conditions. This protocol allows delivery of various tertiary alkyl and benzyl fluorides in an environmentally benign manner.We report an organophotoredox-catalyzed decarboxylative fluorination of alkyl redox active esters with triethylamine trihydrofluoride. The reaction proceeds through a radical-polar crossover mechanism to generate a carbocation equivalent under non-acidic and transition metal free conditions. This protocol allows delivery of various tertiary alkyl and benzyl fluorides in an environmentally benign manner.

A new type of alkylborate was developed for the purpose of generating radicals via direct photoexcitation. These borates were prepared using 2,2′-(pyridine-2,6-diyl)diphenol as a tridentate ligand together with organoboronic acids or potassium trifluoroborates. The ready availability of organoboron compounds is a significant advantage of this direct photoexcitation protocol. The excited states of these borates can also serve as strong reductants, enabling various transformations.

We describe a synthetic approach to sterically hindered α-hydroxy carbonyl compounds through radical–radical coupling. An organic photoredox catalysis reaction converts an aliphatic carboxylic acid and α-ketocarbonyl to a transient alkyl radical and a persistent ketyl radical, respectively, which couple selectively based on the persistent radical effect. This protocol allows the use of primary, secondary, and tertiary aliphatic carboxylic acids to introduce various alkyl substituents onto ketone moieties of α-ketocarbonyls under mild reaction conditions.

This manuscript describes a visible-light-mediated organophotoredox catalytic process for vicinal difunctionalization of alkenes using heteroatom nucleophiles and aliphatic redox active esters. A wide range of heteroatom nucleophiles including alcohols, water, carboxylic acids, amides, and halogens can be used for this reaction. This radical relay type reaction allows forging of C(sp3)–C(sp3) with a carbon-centered radical and C(sp3)–heteroatom bonds with a benzyl cation on the vinylarenes with complete regioselectivity in a single step.

This account describes our work concerning the application of alkylboranes to addition reactions to unsaturated compounds, with catalysis by copper. Alkylboranes are readily obtained from standard alkene hydroboration reactions, which is an advantage of these processes. The substrates can contain a wide range of functional groups. The reactions described herein include the formation of alkylcopper(I) species viathe catalytic B/Cu transmetallation of alkylboranes and subsequent addition to unsaturated carbon–carbon bonds or carbon dioxide.This account describes our work concerning the application of alkylboranes to addition reactions to unsaturated compounds, with catalysis by copper. Alkylboranes are readily obtained from standard alkene hydroboration reactions, which is an advantage of these processes. The substrates can contain a wide range of functional groups. The reactions described herein include the formation of alkylcopper(I) species viathe catalytic B/Cu transmetallation of alkylboranes and subsequent addition to unsaturated carbon–carbon bonds or carbon dioxide.

The KHMDS-catalyzed tertiary alkylation of aldehydes, ketones or imines using tertiary benzylic organoboronates is reported. This protocol permitted the use of tertiary benzylic alkylboronates as the tertiary alkyl anion for construction of highly congested contiguous sp3carbon centers. The mild and transition-metal-free reaction conditions are attractive features of the protocol.The KHMDS-catalyzed tertiary alkylation of aldehydes, ketones or imines using tertiary benzylic organoboronates is reported. This protocol permitted the use of tertiary benzylic alkylboronates as the tertiary alkyl anion for construction of highly congested contiguous sp3carbon centers. The mild and transition-metal-free reaction conditions are attractive features of the protocol.

The generation of tertiary, secondary, and primary alkyl radicals has been achieved by the direct visible-light excitation of a boracene-based alkylborate. This system is based on the photophysical properties of the organoboron molecule. The protocol is applicable to decyanoalkylation, Giese addition, and nickel-catalyzed carbon–carbon bond formations such as alkyl–aryl cross-coupling or vicinal alkylarylation of alkenes, enabling the introduction of various C(sp3) fragments to organic molecules.

An NHC-catalyzed radical relay enabled the vicinal alkylacylation of alkenes using aldehydes and tertiary α-bromo esters as a versatile route to δ-keto esters bearing an all-carbon quaternary center at the position α to the ester. The protocol was applicable to the reaction of tertiary α-bromoamides to afford δ-keto amides. This protocol enabled the conversion of readily available starting materials to congested and functionalized δ-ketocarbonyls in a single step without using transition metals.

5-Membered ring aliphatic oxaboroles revealed unique characteristics in their reactivity with diols. The aliphatic oxaborole derivatives exhibited a higher complexation activity for Alizarin Red S than phenyl-, alkylboronic acid, benzoxaborole, and oxaborin. Furthermore, the sugar recognition ability depended on the chirality of the aliphatic boroles.5-Membered ring aliphatic oxaboroles revealed unique characteristics in their reactivity with diols. The aliphatic oxaborole derivatives exhibited a higher complexation activity for Alizarin Red S than phenyl-, alkylboronic acid, benzoxaborole, and oxaborin. Furthermore, the sugar recognition ability depended on the chirality of the aliphatic boroles.

A copper-catalyzed enantioselective reductive cross-coupling using aromatic aldehydes and imines, producing chiral β-amino alcohols, is described. The catalytic formation of enantioenriched chiral α-alkoxyalkylcopper(I) species from aromatic aldehydes and the subsequent reaction with imine electrophiles are attractive features of this protocol.

This manuscript reports a visible-light-mediated organosulfide catalysis that enables the decarboxylative coupling between simple aliphatic alcohol and tertiary or secondary alkyl carboxylic acid-derived redox active esters to produce a C(sp3)–O–C(sp3) fragment. Results of the coupling using other heteroatom nucleophiles such as water, amides, and thiols are also described.

The synergistic merger of a thiazolium N-heterocyclic carbene (NHC) catalyst and a palladium–bisphosphine catalyst enabled the allylation of aldehyde acyl anions using allylic carbonates as electrophiles. Owing to the mildness of the reaction conditions, various functional groups were tolerated in the substrates.The synergistic merger of a thiazolium N-heterocyclic carbene (NHC) catalyst and a palladium–bisphosphine catalyst enabled the allylation of aldehyde acyl anions using allylic carbonates as electrophiles. Owing to the mildness of the reaction conditions, various functional groups were tolerated in the substrates.

A copper/prolinol-phosphine chiral catalyst enabled the one-step synthesis of chiral α-alkylidene-β-lactams. Optimization of the chiral ligand for steric and electronic properties realized the highly enantioselective coupling of nitrones and propargyl alcohol derived alkynes. The resulting chiral α-alkylidene-β-lactams served as a platform for various β-lactams via well-established transformations of α,β-unsaturated carbonyl compounds.

We found that N-heterocyclic carbene catalysis promoted the unprecedented decarboxylative coupling of aryl aldehydes and tertiary or secondary alkyl carboxylic acid-derived redox-active esters to produce aryl alkyl ketones. The mild and transition-metal-free reaction conditions are attractive features of this method. The power of this protocol was demonstrated by the functionalization of pharmaceutical drugs and natural product. A reaction pathway involving single electron transfer from an enolate form of Breslow intermediate to a redox ester followed by recombination of the resultant radical pair to form a carbon–carbon bond is proposed.

The copper-catalyzed reductive coupling of two different carbonyl compounds has been achieved. The reaction of aromatic aldehydes and arylketones with a silylboronate in the presence of a catalytic amount of a CuCl–N-heterocyclic carbene (NHC) complex and a stoichiometric amount of alkoxide base yielded cross-coupled 1,2-diol derivatives. A reaction pathway is proposed that involves the catalytic formation of a nucleophilic α-silyloxybenzylcopper(I) species from the aromatic aldehyde and its subsequent coupling with the arylketone. This process was amenable to asymmetric catalysis. This copper catalyst system also enabled the reductive coupling between aromatic aldehydes and imines.

The N-heterocyclic carbene-catalyzed radical relay enables the vicinal alkylacylation of styrenes, acrylates and acrylonitrile using aldehydes and tertiary alkyl carboxylic acid-derived redox-active esters. This protocol introduces tertiary alkyl groups and acyl groups to C–C double bonds with complete regioselectivity to produce functionalized ketone derivatives. The radical relay mechanism involves single electron transfer from the enolate form of a Breslow intermediate and radical addition of the resultant alkyl radical to the alkene followed by radical–radical coupling.

We have developed a new umpolung strategy for catalytically forming a chiral α-alkoxyalkyl anion from an aromatic aldehyde for use in asymmetric synthesis. The reaction between aromatic aldehydes and aryl or allyl electrophiles with a silylboronate utilizing a chiral copper–N-heterocyclic carbene catalyst and a palladium–bisphosphine catalyst in a synergistic manner occurred with high enantioselectivities to deliver the three-component coupling products, chiral silyl-protected secondary alcohol derivatives. Our method features the catalytic generation of enantioenriched chiral α-alkoxyalkylcopper(I) intermediates from aldehydes and their subsequent palladium-catalyzed stereospecific cross-coupling.

A reductive C–C-bond-forming cyclization of vinyl-terminated allyl chlorides viaalkene hydroboration with 9-BBN-H followed by Cu-catalyzed asymmetric intramolecular allylic alkylation with a new chiral phosphoramidite ligand produced six-membered ring compounds with a tertiary or quaternary stereogenic center in the ring with high enantioselectivity.A reductive C–C-bond-forming cyclization of vinyl-terminated allyl chlorides viaalkene hydroboration with 9-BBN-H followed by Cu-catalyzed asymmetric intramolecular allylic alkylation with a new chiral phosphoramidite ligand produced six-membered ring compounds with a tertiary or quaternary stereogenic center in the ring with high enantioselectivity.

Merging N-heterocyclic carbene catalysis with photoredox proton-coupled electron transfer (PCET) has enabled the amidoacylation of alkenes for the construction of a sterically congested cyclic β-amido ketone skeleton bearing α-tertiary or -quaternary carbon centers with high diastereoselectivity. The reaction involves generating amidyl radicals via oxidative PCET under photoredox catalysis, followed by rapid intramolecular cyclization to form the carbon-centered radical. Precise control of electron transfer in the two-radical-generation mechanisms is required for achieving this diastereoselective radical-radical coupling. The photocatalyst 3CzClIPN greatly facilitates this reaction because of its high oxidation potential and moderate reduction potential. The correlation between the redox potential of the photocatalyst and the yield provides an analogy for the reaction mechanism. Further transformation of the product affords acyclic 3-aminobutane-1,4-diol as a single diastereomer. This protocol allows the mild synthesis of structurally crowded bioactive molecules.

A synergistic action of a thiazolium N‐heterocyclic carbene catalyst and a palladium–bisphosphine catalyst has enabled the allylation between aldehydes acyl anions and allylic amines to afford β,γ‐unsaturated ketones, which are versatile synthetic intermediates for organic synthesis. A synergistic actionof a thiazolium N‐heterocyclic carbene catalyst and a palladium‐bisphosphine catalyst has enabled the allylation between aldehydes acyl anions and allylic amines to afford β,γ‐unsaturated ketones, which are versatile building blocks for organic synthesis.

Photo-caged methodologies have been indispensable for elucidating the functional mechanisms of pharmacologically active molecules at the cellular level. A photo-triggered removable unit enables control of the photo-induced expression of pharmacologically active molecular function, resulting in a rapid increase in the concentration of the bioactive compound near the target cell. However, caging the target bioactive compound generally requires specific heteroatom-based functional groups, limiting the types of molecular structures that can be caged. We have developed an unprecedented methodology for caging/uncaging on carbon atoms using a unit with a photo-cleavable carbon–boron bond. The caging/uncaging process requires installation of the CH2–B group on the nitrogen atom that formally assembles an N-methyl group protected with a photoremovable unit. N-Methylation proceeds by photoirradiation via carbon-centered radical generation. Using this radical caging strategy to cage previously uncageable bioactive molecules, we have photocaged molecules with no general labeling sites, including acetylcholine, an endogenous neurotransmitter. Caged acetylcholine provides an unconventional tool for optopharmacology to clarify neuronal mechanisms on the basis of photo-regulating acetylcholine localization. We demonstrated the utility of this probe by monitoring uncaging in HEK cells expressing a biosensor to detect ACh on the cell surface, as well as Ca2+imaging in Drosophilabrain cells (ex vivo).