Cation Radical-Accelerated Nucleophilic Aromatic Substitution for Amination of Alkoxyarenes

Nucleophilic aromatic substitution (SNAr) is a common method for arene functionalization; however, reactions of this type are typically limited to electron-deficient aromatic halides. Herein, we describe a mild, metal-free, cation-radical accelerated nucleophilic aromatic substitution (CRA-SNAr) using a potent, highly oxidizing acridinium photoredox catalyst. Selective substitution of arene C-O bonds on a wide array of aryl ether substrates was shown with a variety of primary amine nucleophiles. Mechanistic evidence is also presented that supports the proposed CRA-SNAr pathway

Nucleophilic Aromatic Substitution of Unactivated Fluoroarenes Enabled by Organic Photoredox Catalysis

Nucleophilic aromatic substitution (SNAr) is a classical reaction with well-known reactivity toward electron-poor fluoroarenes. However, electron-neutral and electron-rich fluoro(hetero)arenes are considerably underrepresented. Herein, we present a method for the nucleophilic defluorination of unactivated fluoroarenes enabled by cation radical-accelerated nucleophilic aromatic substitution. The use of organic photoredox catalysis renders this method operationally simple under mild conditions and is amenable to various nucleophile classes, including azoles, amines, and carboxylic acids. Select fluorinated heterocycles can be functionalized using this method. In addition, the late-stage functionalization of pharmaceuticals is also presented. Computational studies demonstrate that the site selectivity of the reaction is dictated by arene electronics

Direct Catalytic Anti-Markovnikov Hydroetherification of Alkenols

A direct intramolecular anti-Markovnikov hydroetherification reaction of alkenols is described. By employing catalytic quantities of commercially-available 9-mesityl-10-methylacridinium perchlorate and 2-phenylmalononitrile as a redox-cycling source of a hydrogen atom, we report the anti-Markovnikov hydroetherification of alkenes with complete regioselectivity. In addition, we present results demonstrating that this novel catalytic system can be applied to the anti-Markovnikov hydrolactonization of alkenoic acids

Synthesis of cyclobutane lignans via an organic single electron oxidant–electron relay system

A direct method to synthesize lignan cyclobutanes and analogs via photoinduced electron transfer is presented. A variety of oxygenated alkenes are employed to furnish terminal or substituted cyclobutane adducts with complete regiocontrol, yielding cycloadducts with trans stereochemistry. Key to minimizing competing cycloreversion is the inclusion of an aromatic electron relay (ER). This method has been adapted to the synthesis of the natural products magnosalin and pellucidin A

Mechanistic Insight into the Photoredox Catalysis of Anti-Markovnikov Alkene Hydrofunctionalization Reactions

We describe our efforts to understand the key mechanistic aspects of the previously reported alkene hydrofunctionalization reactions using 9-mesityl-10-methylacridinium (Mes-Acr+) as a photoredox catalyst. Importantly, we are able to detect alkene cation radical intermediates, and confirm that phenylthiyl radical is capable of oxidizing the persistent acridinyl radical in a fast process that unites the catalytic activity of the photoredox and hydrogen atom transfer (HAT) manifolds. Additionally, we present evidence that diphenyl disulfide ((PhS)2) operates on a common catalytic cycle with thiophenol (PhSH) by way of photolytic cleaveage of the disulfide bond. Transition structure analysis of the HAT step using DFT reveals that the activation barrier for H atom donation from PhSH is significantly lower than 2-phenylmalononitrile (PMN) due to structural reorganization. In the early stages of the reaction, Mes-Acr+ is observed to engage in off-cycle adduct formation, presumably as buildup of PhS− becomes significant. The kinetic differences between PhSH and (PhS)2 as HAT catalysts indicate that the proton transfer step may have significant rate limiting influence

Three-Component Coupling Reactions of Silylglyoxylates, Alkynes, and Aldehydes: A Chemoselective One-Step Glycolate Aldol Construction

A single-pot three-component coupling reaction of silylglyoxylates (1), terminal alkynes, and aldehydes in the presence of ZnI2 and Et3N is presented. The products of the reaction, densely functionalized silyl-protected glycolate aldols (2), can be converted to the corresponding acetonides (3) in a one-pot deprotection/ketalization sequence. A variety of terminal alkynes and aldehydes can be successfully employed to give a range of highly functionalized, fully protected 1,2-diols in good yields and moderate diastereoselectivities. Mechanistic experiments suggest that the zinc acetylide reacts with the silylgyloxylate (1) in a chemoselective manner. Using an unoptimized (+)-N-methylephedrine and Zn(OTf)2 system, silyl-deprotected adduct 2 was formed in 64% ee and 89:11 dr

Anti-Markovnikov Hydroamination of Alkenes Catalyzed by an Organic Photoredox System

Herein we report a metal-free method for the direct anti-Markovnikov hydroamination of unsaturated amines. Irradiation of the amine substrates with visible light in the presence of catalytic quantities of easily synthesized 9-mesityl-10-methylacridinium tetrafluoroborate and thiophenol as a hydrogen atom donor furnished the nitrogen containing heterocycles with complete regio-control. Two examples of in termolecular anti-Markovnikov alkene hydroamination are also disclosed

Divergent regioselectivity in photoredox-catalyzed hydrofunctionalization reactions of unsaturated amides and thioamides

A direct method to construct 2-oxazolines and 2-thiazolines from corresponding allylic amides and thioamides is reported

Direct Catalytic Anti-Markovnikov Addition of Carboxylic Acids to Alkenes

A direct catalytic anti-Markovnikov addition of carboxylic acids to alkenes is reported. The catalyst system is comprised of the Fukuzumi acridinium photooxidant (1) and a substoichiometric quantity of a hydrogen atom donor. Oxidizable olefins such as styrenes, trisubstituted aliphatic alkenes, and enamides can be employed along with a variety of carboxylic acids to afford the anti-Markovnikov addition adducts exclusively. A deuterium-labeling experiment lends insight to the potential mechanism