p-Methoxybenzyl-Radical-Promoted Chemoselective Protection of sec-Alkylamides.

The hitherto difficult site-selective p-methoxybenzylation of secondary amides using p-methoxybenzylated alkylsilyl peroxides as a novel p-methoxybenzylation agent under copper catalysis is reported. The reaction proceeds under mild reaction conditions in a highly chemoselective manner. This approach was successfully applied to the site-selective p-methoxybenzylation of peptides.

Fe-Catalyzed Three-Component Coupling Reaction of α,ß,γ,δ-Unsaturated Carbonyl Compounds and Conjugate Dienes with Alkylsilyl Peroxides and Nucleophiles.

An Fe(OTf)2-catalyzed three-component coupling reaction of α,ß,γ,δ-unsaturated carbonyl compounds with alkylsilyl peroxides in the presence of certain heteronucleophiles (ROH and indole) is realized under mild reaction conditions. A variety of α,ß,γ,δ-diene carbonyl substrates with different substituents were successfully employable via combination with several different alkylsilyl peroxides. This new approach is also applicable to the double functionalization of diene substrates.

The copper-catalyzed selective monoalkylation of active methylene compounds with alkylsilyl peroxides.

A novel method for a mild copper-catalyzed selective monoalkylation of active methylene compounds with various alkylsilyl peroxides has been developed. The reaction has a broad substrate scope and our mechanistic studies suggest the participation of radical species in this alkylation reaction.

Design of Bowl-Shaped N-Hydroxyimide Derivatives as New Organoradical Catalysts for Site-Selective C(sp3 )-H Bond Functionalization Reactions.

A series of new bowl-shaped N-hydroxyimide derivatives has been designed and used as selective organoradical catalysts. A number of these bowl-shaped N-hydroxyimide derivatives exhibit excellent site-selectivity in the amination of benzylic C(sp3 )-H bonds in aromatic hydrocarbon substrates.

Cooperative N-heterocyclic carbene/Brønsted acid catalysis for the tail-to-tail (co)dimerization of methacrylonitrile.

The first tail-to-tail dimerization of methacrylonitrile (MAN) has been realized by the cooperative use of N-heterocyclic carbene (NHC) and Brønsted acid catalysts, producing 2,5-dimethylhex-2-enedinitrile with the E/Z ratio of 24:76. Although the NHC alone was not effective for the catalysis, the addition of alcohols resulted in the significant increase of the dimer yield up to 82% in the presence of 5 mol % NHC. Detailed experimental studies including the ESI-MS analysis of the intermediates, stoichiometric (co)dimerizations, and deuterium-labeling experiments revealed the mechanistic aspects of the proton transfer, isomerization, umpolung, and rate-limiting steps, allowing us to observe several mechanistic differences between the dimerization of MAN and that of methyl methacrylate. The stoichiometric reactions in the presence and absence of an alcohol suggest that the alcohol additives play a role in promoting the intermolecular proton transfers from the deoxy-Breslow intermediate to the regenerated NHC in the second half of the catalytic cycle. In addition, the codimerizations of MAN with n-butyl methacrylate (n-BuMA) have been studied. While the dimerization of n-BuMA was sluggish in the presence of an alcohol, the catalytic activity for the codimerization was enhanced by the cooperative systems.

Synthetic utility of functionalized alkylsilyl peroxides for Fe-catalyzed and visible-light-promoted radical transformation.

α-Keto-, ß-acetoxy- and ß-amidoalkylsilyl peroxides are prepared from various precursors and utilized for Fe-catalyzed and visible-light-promoted radical functionalization with coupling partners under mild conditions with a broad substrate scope.

Asymmetric Phase-Transfer Alkylation of Readily Available Aryl Aldehyde Schiff Bases of Amino Acid Ethyl Esters.

Asymmetric phase-transfer alkylation of the N-(arylmethylene)-α-alkylamino acid ethyl esters and N-(arylmethylene)glycine ethyl esters was found to be catalyzed by the (R)- or (S)-Simplified Maruoka Catalyst with high efficiency and excellent enantioselectivity. This approach was successfully applied to the enantioselective formal synthesis of the angiotensin II type 2 receptor (AT2R) antagonists Olodanrigan and LX9211, and the practical aspect is demonstrated by the kilogram-scale synthesis of a key intermediate for the synthesis of LX9211.

Experimental mechanistic studies of the tail-to-tail dimerization of methyl methacrylate catalyzed by N-heterocyclic carbene.

We and others have previously reported the intermolecular umpolung reactions of Michael acceptors catalyzed by an N-heterocyclic carbene (NHC). The representative tail-to-tail dimerization of methyl methacrylate (MMA) has now been intensively investigated, leading to the following conclusions: (1) The catalysis involves the deoxy-Breslow intermediate, which is quite stable and remains active after the catalysis. (2) Addition of the intermediate to MMA and the final catalyst elimination are the rate-limiting steps. Addition of the NHC to MMA and the proton transfers are relatively very rapid. (3) The two alkenyl protons of the first MMA undergo an intermolecular transfer to C3 and C5 of the dimer. (4) The initial proton transfer is intermolecular. (5) Compared with the benzoin condensation, noticeable differences in the kinetics, reversibility, and stability of the intermediates are observed.

Synthetic Utility of Alkyl tert-Butyl Peroxides in a Copper-Catalyzed Radical Functionalization.

Alkyl tert-butyl peroxides are prepared from the corresponding tert-alkyl precursors and tert-butyl hydroperoxide in the presence of a promoter. These substrates can be utilized in a mild copper-catalyzed radical functionalization that utilizes several coupling partners and has a broad substrate scope. A mechanistic study suggests that alkyl radical species participate in the coupling reactions.

Selective functionalization of benzylic C-H bonds of two different benzylic ethers by bowl-shaped N-hydroxyimide derivatives as efficient organoradical catalysts.

A highly efficient, site-selective benzylic C-H bond amination of two different benzylic ether substrates was described by using bowl-shaped N-hydroxyimide organoradical catalysts with diethyl azodicarboxylate. The synthetic utility of this approach is demonstrated by the subsequent transformation of the amination products into the corresponding aldehydes and alkylhydrazines.

Fe-Catalyzed Dicarbofunctionalization of Vinylarenes with Alkylsilyl Peroxides and ß-Keto Carbonyl Substrates.

The formation of two carbon-carbon bonds using vinylarenes with alkylsilyl peroxides and ß-keto carbonyl substrates is effected by the presence of catalytic Fe(OTf)2 under mild reaction conditions. A variety of vinylarenes with different substituents can be utilized in combination with several different alkylsilyl peroxides and ß-keto carbonyl substrates.

The Formation of C-C or C-N Bonds via the Copper-Catalyzed Coupling of Alkylsilyl Peroxides and Organosilicon Compounds: A Route to Perfluoroalkylation.

The copper-catalyzed selective cleavage of alkylsilyl peroxides and the subsequent formation of carbon-carbon or carbon-nitrogen bonds with organosilicon compounds are described. The reaction proceeds under mild conditions and exhibits a broad substrate scope with respect to both cyclic and acyclic alkylsilyl peroxides in combination with carbon and nitrogen sources. In particular, this approach enables the facile radical perfluoroalkylation using commercially available perfluoroalkyltrimethylsilanes. Our mechanistic studies suggest that the reaction should proceed via a free-radical process.

Synthesis of Functionalized Organoboron/Silicon Compounds by Copper-Catalyzed Coupling of Alkylsilyl Peroxides and Diboron/Silylborane Reagents.

The facile synthesis of functionalized organoboron/silicon compounds by copper-catalyzed coupling of alkylsilyl peroxides and diboron/silylborane reagents is reported. The reactions proceed smoothly under mild, neutral conditions in short reaction times to generate organoboron/silicon compounds bearing a ketone moiety, which are useful synthetic intermediates that are otherwise difficult to access. The results of mechanistic investigations suggest the radical-mediated formation of carbon-boron and carbon-silicon bonds via ß-scission of alkoxy radicals.

Iodine(III)-Catalyzed Electrophilic Nitration of Phenols via Non-Brønsted Acidic NO2+ Generation.

The first catalytic procedure for the electrophilic nitration of phenols was developed using iodosylbenzene as an organocatalyst based on iodine(III) and aluminum nitrate as a nitro group source. This atom-economic protocol occurs under mild, non-Brønsted acidic and open-flask reaction conditions with a broad functional-group tolerance including several heterocycles. Density functional theory (DFT) calculations at the (SMD:MeCN)Mo8-HX/(LANLo8+f,6-311+G*) level indicated that the reaction proceeds through a cationic pathway that efficiently generates the NO2+ ion, which is the nitrating species under neutral conditions.

Copper-Catalyzed C(sp)-C(sp3) Coupling of Terminal Alkynes with Alkylsilyl Peroxides via a Radical Mechanism.

A copper-catalyzed C(sp)-C(sp3) coupling reaction between terminal alkynes and alkylsilyl peroxides is reported. In the presence of a copper catalyst and 4-dimethylaminopyridine, the reaction smoothly affords a variety of internal alkynes by coupling alkylsilyl peroxides and terminal alkynes. Mechanistic studies suggest that the reaction proceeds via a radical mechanism, whereby the alkyl radicals are generated from the alkylsilyl peroxides. The present transformation represents a rare example of a radical-mediated C(sp)-C(sp3) coupling reaction of terminal alkynes.

N-Heterocyclic carbene-mediated redox condensation of alcohols.

N-Heterocyclic carbenes (NHCs) with a variety of oxidants promote the Mitsunobu-type coupling reactions of alcohols with phenols, carboxylic acids, and phthalimide. Experiments using a chiral alcohol indicate that these reactions proceed via SN1 or SN2 pathways depending on the polarity of the used solvents. The NHCs are consumed as reducing reagents to form their oxides as readily separable byproducts.

Transfer hydrogenation promoted by N-heterocyclic carbene and water.

N-Heterocyclic carbenes (NHCs) promote the transfer hydrogenation of various activated C=C, C=N, and N=N bonds with water as the proton source. The NHCs act as reducing reagents to be converted into their oxides. A detailed reaction mechanism is proposed on the basis of deuterium-labeling experiments.