Benzoic Acid Serves as Precursor of Catalytic HAT Reagent in a Two-Molecule Photoredox System.

The photoinduced regioselective HAT reactions of acetals, ethers, and alcohols using benzoic acids in a two-molecule photoredox system led to the formation of new C-C bonds with alkenes under mild conditions. Aryl carboxy radicals generated from benzoic acids in a two-molecule photoredox system can function as catalytic HAT reagents, even though an excess amount of a hydrogen donor substrate is required. Various acetals, ethers, alcohols, and alkenes can be employed in the photoreaction to provide both high yields of adducts and high recoveries of benzoic acids.

Palladium-Catalyzed anti-Michael-Type (Hetero)arylation of Acrylamides.

This paper reports a direct α-(hetero)arylation of acrylamides through an inverse electron-demand nucleophilic addition, specifically an anti-Michael-type addition. The introduction of a quinolyl directing group facilitates the nucleophilic addition of (hetero)arenes to the α-position of acrylamides. The quinolyl directing group effectively suppresses undesired ß-hydrogen elimination and is removable for subsequent derivatization. The presented method provides an atom economical synthesis of α-(hetero)arylamide with a high degree of functional group tolerance.

Double difunctionalization of vinyl ether tethered nucleophile with electron-deficient alkene in two-molecule photoredox system.

Double difunctionalization of a vinyl ether tethered hydroxy or carbamoyl group with electron-deficient alkenes such as acrylonitrile or acrylic esters was achieved by visible-light irradiation in a two-molecule photoredox system. Use of anhydrous acetonitrile solution as a solvent promoted both dimerization of the radical cation of electron-rich alkene with electron-rich alkene and intramolecular nucleophilic addition to generate an electron-rich radical that was added to electron-deficient alkene to furnish the double difunctionalized product. A variety of electronically differentiated rich and deficient alkenes were used in the photoreaction; a simple construction of a complex carbon framework containing acetal from simple alkenes was successful under mild conditions.

Rhodium-catalysed additive-free alkoxycarbonylation of indoles: 2,4,6-trimethylbenzoic acid-based carbonate anhydrides as a versatile alkoxycarboxyl source.

We report a CO-free approach to indole-2-carboxylic esters: rhodium-catalysed C(2)-alkoxycarbonylation of indoles with 2,4,6-trimethylbenzoic acid-based carbonate anhydrides. Selective C-O bond cleavage of the anhydrides facilitates the introduction of various alkoxycarbonyl groups. Control experiments suggest that merging a rhodium catalyst and KI promotes the in situ formation of the RhI species.

Amide-Directed Rhodium-Catalyzed Chain-Walking Hydrothiolation of Internal Alkenes.

We developed a rhodium-catalyzed chain-walking hydrothiolation process for internal alkenes, which offers a novel and efficient alternative for C(sp3)-H bond cleavage, while focusing on thiol incorporation. This method exclusively affords N,S-acetals at 36-90% yields. Regioconvergent hydrothiolation significantly improved the effectiveness of this transformation. Preliminary mechanistic investigations revealed that an amide-directing group is essential for regioselective synthesis, underlining its significance in this process.

Rhodium-catalysed additive-free carbonylation of benzamides with diethyl dicarbonate as a carbonyl source.

Phthalimides are prevalent in numerous pharmaceuticals, prompting various phthalimide syntheses through C-H activation. Nevertheless, the necessity for stoichiometric additives limits their practicality and versatility. Herein, we introduced diethyl dicarbonate as a carbonyl source for an additive-free carbonylation of benzamides. This transformation signifies an operationally simple and CO-free phthalimide synthesis.

Diastereo- and Enantioselective Reductive Mannich-type Reaction of α,ß-Unsaturated Carboxylic Acids to Ketimines: A Direct Entry to Unprotected ß2,3,3 -Amino Acids.

Stereoselective construction of unprotected ß-amino acids is a significant challenge owing to the lack of methods for the catalytic generation of highly enantioenriched carboxylic acid enolates. In this study, a novel copper-catalyzed diastereo- and enantioselective reductive Mannich-type reaction of α,ß-unsaturated carboxylic acids was developed, which provides a direct and scalable synthetic method for enantioenriched ß2,3,3 -amino acids with vicinal stereogenic centers. The protocol features in situ generation of transiently protected carboxylic acids by a hydrosilane and their diastereo- and enantioselective reductive coupling with ketimines. The synthetic utility of this process was demonstrated by a gram-scale reaction and the transformation of ß-amino acids.

Rhodium-catalysed decarbonylative C(sp2)-H alkylation of indolines with alkyl carboxylic acids and carboxylic anhydrides under redox-neutral conditions.

We developed a rhodium-catalysed decarbonylative C(sp2)-H alkylation method for indolines. This reaction facilitates the use of alkyl carboxylic acids and their anhydrides as a cheap, abundant and non-toxic alkyl source under redox-neutral conditions, featuring the introduction of a primary alkyl chain, which cannot be addressed by previous radical-mediated decarboxylative reaction. Through a mechanistic investigation, we revealed that an initially formed C-7 acylated indoline was transformed into the corresponding alkylated indoline via a decarbonylation process.

Rhodium-Catalyzed C(sp2)-H Alkoxycarbonylation/Acylation of Indolines with Anhydrides as a Carbonyl Source.

We developed rhodium-catalyzed alkoxylcarbonylation/acylation of indolines using anhydrides as a safe and easy-to-handle carbonyl source. This catalytic process represents an additive- and CO-free carbonylation, establishing a simple and straightforward protocol for synthesizing C7-carbonylated indolines. Notably, this reaction provides a successful example of C-H acylation of indolines that results in the formation of α-branched ketones, which were difficult to prepare by previously reported analogous catalytic reactions.

Copper-Catalyzed Enantioselective Reductive Aldol Reaction of α,ß-Unsaturated Carboxylic Acids to Alkyl Aryl Ketones: Silanes as Activator and Transient Protecting Group.

The first enantioselective reductive aldol reaction of unprotected α,ß-unsaturated carboxylic acids was developed by employing a copper/bisphosphine catalyst. The reaction features in situ protection and activation of an α,ß-unsaturated carboxylic acid by a hydrosilane. The copper enolate formed in situ reacts with an alkyl aryl ketone to afford the ß-hydroxy carboxylic acid with excellent enantioselectivity (up to 99 % ee). The corresponding gram-scale reaction with a low catalyst loading and the derivatization of the ß-hydroxy carboxylic acids highlight the practicality of this transformation.

Dealkoxylation of N-alkoxyamides without an external reductant driven by Pd/Al cooperative catalysis.

Lewis acid-assisted palladium-catalysed dealkoxylation of N-alkoxyamides has been developed. This reaction proceeded smoothly with a range of N-alkoxyamides in the absence of an external reductant, thereby establishing a convenient and reductant-free protocol. In addition, a gram-scale reaction could be achieved. Preliminary mechanistic investigations indicated that ß-hydrogen elimination from a palladium alkoxide intermediate generated an intramolecular hydride source.

Catalytic alkylation reactions of weakly acidic carbonyl and related compounds using alkenes as electrophiles.

Catalytic alkylation reactions of weakly acidic carbonyl and related pronucleophiles such as amides, esters, and sulfonamides with substituted alkenes have been reported. In the presence of a strong Brønsted base catalyst system, potassium hexamethyldisilazide and 18-crown-6 ether, the desired reactions proceeded in high yields at ambient temperature with a wide substrate scope. These are atom-economical catalytic alkylation reactions of carbonyl and related compounds.

Catalytic Direct-Type Addition Reactions of Alkylarenes with Imines and Alkenes.

Catalytic addition reactions of very weakly acidic nonactivated alkylarenes such as toluene and its derivatives were developed by using a strongly basic mixed catalyst system under mild reaction conditions. The addition reactions with imines and alkenes proceeded smoothly under proton-transfer conditions to afford the desired products in good to high yields, and high levels of regio- and stereoselectivity were achieved. It was also revealed that the asymmetric addition reaction of an alkylarene was possible.

Catalytic Direct-type 1,4-Addition Reactions of Alkylazaarenes.

1,4-addition reactions of alkylazaarenes catalyzed by strong Brønsted bases have been developed for the first time. The desired reactions with α,ß-unsaturated amides proceeded under mild reaction conditions to give the 1,4-adducts in high yields. Both ortho- and para-substituted azaarenes afforded the desired adducts in high yields. Regioselective reactions of di- or trimethylpyridine were found to be possible depending on the acidity of the α-hydrogen atoms. Furthermore, a candidate of allosteric protein kinase modulators was synthesized in two steps. An asymmetric variant of this reaction was also found to be feasible.

Catalytic Asymmetric 1,4-Addition Reactions of Simple Alkylnitriles.

The development of catalytic asymmetric carbon-carbon bond-forming reactions of alkylnitriles that do not have an activating group at the α-position, under proton-transfer conditions, is a challenging research topic. Here, we report catalytic asymmetric direct-type 1,4-addition reactions of alkylnitriles with α,ß-unsaturated amides by using a catalytic amount of potassium hexamethyldisilazide (KHMDS) with a chiral macro crown ether. The desired reactions proceeded in high yields with good diastereo- and enantioselectivities. To our knowledge, this is the first example of catalytic asymmetric direct-type 1,4-addition reaction of alkylnitriles without any activating group at the α-position.

Catalytic asymmetric direct-type 1,4-addition reactions of simple amides.

The development of catalytic asymmetric direct-type reactions of less acidic carbonyl compounds such as amides and esters has been a challenging theme in organic chemistry for decades. Here we describe the asymmetric direct 1,4-addition reactions of simple amides with α,ß-unsaturated carbonyl compounds using a catalytic amount of a novel chiral catalyst consisting of a potassium base and a macrocyclic chiral crown ether. The desired 1,5-dicarbonyl compounds were obtained in high yields with excellent diastereo- and enantioselectivities. This is the first example of a highly enantioselective catalytic direct-type reaction of simple amides. In addition, the structure of the chiral potassium catalyst has been investigated by X-ray crystallographic, dynamic (1)H NMR, and MALDI-TOF MS analyses.

Development of strong Brønsted base catalysis: catalytic direct-type Mannich reactions of non-activated esters via a product-base mechanism.

A catalytic Mannich reaction of a simple ester with no activating functionality at the α-position via a product-base mechanism was reported. The desired Mannich adducts were obtained in high yields using a catalytic amount of KH. This is a rare example of a Brønsted base-catalyzed Mannich reaction of unactivated esters as substrates.