Acid-Catalyzed Oxy-aminomethylation of Styrenes.

We report a strong Brønsted acid-catalyzed three-component oxy-aminomethylation of styrenes with -trioxane and sulfonamides or carbamates. This transformation provides a variety of 1,3-oxazinanes in moderate to good yields under mild reaction conditions. The obtained heterocycles can be readily transformed into the corresponding 1,3-amino alcohols, which are useful building blocks for the synthesis of pharmaceutically relevant molecules.

Formation of Breslow Intermediates from N-Heterocyclic Carbenes and Aldehydes Involves Autocatalysis by the Breslow Intermediate, and a Hemiacetal.

Under aprotic conditions, the stoichiometric reaction of N-heterocyclic carbenes (NHCs) such as imidazolidin-2-ylidenes with aldehydes affords Breslow Intermediates (BIs), involving a formal 1,2-C-to-O proton shift. We herein report kinetic studies (NMR), complemented by DFT calculations, on the mechanism of this kinetically disfavored H-translocation. Variable time normalization analysis (VTNA) revealed that the kinetic orders of the reactants vary for different NHC-to-aldehyde ratios, indicating different and ratio-dependent mechanistic regimes.

Additions of Aldehyde-Derived Radicals and Nucleophilic -Alkylindoles to Styrenes by Photoredox Catalysis.

The consecutive addition of acyl radicals and -alkylindole nucleophiles to styrenes was established, as well as some additional radical-nucleophile combinations. Both aryl and aliphatic aldehydes give reasonable yields. The reaction proceeds best for α-substituted styrenes, effectively creating a quaternary all-carbon center.

Acid promoted radical-chain difunctionalization of styrenes with stabilized radicals and (N,O)-nucleophiles.

A difunctionalization of alkenes through sequential addition of a radical and a nucleophile has been developed, which is suggested to proceed by a radical chain mechanism not requiring a catalyst. An electron transfer step to the oxidant benzoyl peroxide is facilitated by protonation with a strong acid.

Investigating the Oxidation Step in the CuCl-Catalyzed Aerobic Oxidative Coupling Reaction of -Aryl Tetrahydroisoquinolines.

The oxidative coupling of -aryl tetrahydroisoquinolines with nucleophiles has inspired the development of novel C-H functionalization reactions as well as mechanistic studies. Here, we investigate the oxidation step that forms iminium ions as key intermediates in the method using CuCl as the catalyst and oxygen as the terminal oxidant. A strong electronic effect of substituents in the N-aryl ring was found by synthetic studies and a Hammett plot analysis, supporting initial electron transfer from the amine to Cu(II).

Aldehydes as Alkylating Agents for Ketones.

Common and non-toxic aldehydes are proposed as reagents for alkylation of ketones instead of carcinogenic alkyl halides. The developed reductive alkylation reaction proceeds in the presence of the commercially available ruthenium catalyst [(cymene)RuCl ] (as low as 250 ppm) and carbon monoxide as the reducing agent. The reaction works well for a broad substrate scope, including aromatic and aliphatic aldehydes and ketones.

Philicity of Acetonyl and Benzoyl Radicals: A Comparative Experimental and Computational Study.

In this work, the reactivities of acetonyl and benzoyl radicals in aromatic substitution and addition reactions have been compared in an experimental and computational study. The results show that acetonyl is more electrophilic than benzoyl, which is rather nucleophilic. A Hammett plot analysis of the addition reactions of the two radicals to substituted styrenes clearly support the nucleophilicity of benzoyl, but in the case of acetonyl, no satisfactory linear correlation with a single substituent-related parameter was found.

Molecular Radical Chain Initiators for Ambient- to Low-Temperature Applications.

An overview of methods for the initiation of radical chain reactions by specific initiator compounds, which generate radicals, is given. These can be utilized to initiate any kind of radical chain reaction by transforming substrates into the desired radical intermediates. Azo initiators, peroxides, nitroxides, trialkylboranes, dialkyl zinc compounds, and type I photoinitiators are discussed, as well as methods of redox- and sonochemical initiation.

Alkenyl and Aryl Peroxides.

Alkenyl and aryl peroxides are a special class of organic peroxides. Under ambient conditions, they are usually short-lived, rapidly decomposing into radicals by homolytic O-O bond cleavage. They play an important role in the chemistry of the lower atmosphere, where they are formed through ozonolysis of alkenes.

Reaction Mechanism of Iodine-Catalyzed Michael Additions.

Molecular iodine, an easy to handle solid, has been successfully employed as a catalyst in different organic transformations for more than 100 years. Despite being active even in very small amounts, the origin of this remarkable catalytic effect is still unknown. Both a halogen bond mechanism as well as hidden Brønsted acid catalysis are frequently discussed as possible explanations.

Acid-Catalyzed Activation of Peroxyketals: Tunable Radical Initiation at Ambient Temperature and Below.

This study details how peroxyketals, commercially available thermal initiators, and structurally related peroxides are activated in the presence of an acid catalyst to generate radicals at room temperature and below. This simple combination of two substrates was shown to efficiently initiate a variety of radical processes. This phenomenon is rationalized by the acid-catalyzed in situ formation of highly unstable alkenyl peroxides which readily decompose into initiating radical species.

Asymmetric counteranion-directed Lewis acid organocatalysis for the scalable cyanosilylation of aldehydes.

Due to the high versatility of chiral cyanohydrins, the catalytic asymmetric cyanation reaction of carbonyl compounds has attracted widespread interest. However, efficient protocols that function at a preparative scale with low catalyst loading are still rare. Here, asymmetric counteranion-directed Lewis acid organocatalysis proves to be remarkably successful in addressing this problem and enabled a molar-scale cyanosilylation in quantitative yield and with excellent enantioselectivity.

Acid-Mediated Formation of Radicals or Baeyer-Villiger Oxidation from Criegee Adducts.

The acid-mediated reaction of ketones with hydroperoxides generates radicals, a process with reaction conditions similar to those of the Baeyer-Villiger oxidation but with an outcome resembling the formation of hydroxyl radicals via ozonolysis in the atmosphere. The Baeyer-Villiger oxidation forms esters from ketones, with the preferred use of peracids. In contrast, alkyl hydroperoxides and hydrogen peroxide react with ketones by condensation to form alkenyl peroxides, which rapidly undergo homolytic O-O bond cleavage to form radicals.

Experimental and computational studies on the C-H amination mechanism of tetrahydrocarbazoles via hydroperoxides.

The acid-catalyzed reactions of photochemically generated tetrahydrocarbazole peroxides with anilines have been studied experimentally and computationally to identify the underlying reaction mechanism. The kinetic data indicate a reaction order of one in the hydroperoxide and zero in the aniline. Computational investigations using density functional theory support the experimental findings and predict an initial tautomerization between an imine and enamine substructure of the primarily generated tetrahydrocarbazole peroxide to be the rate controlling step.

Reaction progress kinetic analysis of a copper-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline.

The results from a kinetic investigation of a Cu-catalyzed oxidative coupling reaction between N-phenyl tetrahydroisoquinoline and a silyl enol ether using elemental oxygen as oxidant are presented. By using reaction progress kinetic analysis as an evaluation method for the obtained data, we discovered information regarding the reaction order of the substrates and catalysts. Based on this information and some additional experiments, a refined model for the initial oxidative activation of the amine substrate and the activation of the nucleophile by the catalyst was developed.

Synthesis of antiviral tetrahydrocarbazole derivatives by photochemical and acid-catalyzed C-H functionalization via intermediate peroxides (CHIPS).

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry.

Acid-catalyzed oxidative radical addition of ketones to olefins.

Based on a mechanistic study, we have discovered a Brønsted acid catalyzed formation of ketone radicals. This is believed to proceed via thermally labile alkenyl peroxides formed in situ from ketones and hydroperoxides. The discovery could be utilized to develop a multicomponent radical addition of unactivated ketones and tert-butyl hydroperoxide to olefins.

Aerobic C-H amination of tetrahydrocarbazole derivatives via photochemically generated hydroperoxides.

A Brønsted acid catalyzed C-H functionalization via Intermediate PeroxideS (CHIPS), generated photochemically, allows the oxidative coupling of indole derivatives with a variety of nitrogen nucleophiles. The reaction can be performed in one pot and requires only visible light, elemental oxygen, a Brønsted acid and a photosensitizer. The method can be applied to an efficient synthesis of some biologically active compounds.

A comparative mechanistic study of Cu-catalyzed oxidative coupling reactions with N-phenyltetrahydroisoquinoline.

A comparative mechanistic study of Cu-catalyzed oxidative coupling reactions of N-phenyltetrahydroisoquinoline with different nucleophiles was conducted. Two previously reported combinations of catalyst and oxidant were studied, CuCl(2)·2H(2)O/O(2) and CuBr/tert-butyl hydroperoxide (TBHP). On the basis of a synthetic study with different nucleophiles, the electrophilicity of the intermediate iminium ion was estimated and differences between the two methods were revealed.

Mechanistic studies on a Cu-catalyzed aerobic oxidative coupling reaction with N-phenyl tetrahydroisoquinoline: structure of intermediates and the role of methanol as a solvent.

The mechanism of an aerobic copper-catalyzed oxidative coupling reaction with N-phenyl tetrahydroisoquinoline was investigated. The oxidized species formed from the reaction of the amine with the copper catalyst were analyzed by NMR-spectroscopy. An iminium dichlorocuprate was found to be the reactive intermediate and could be structurally characterized by X-ray crystallography.

Lewis acid-catalysed one pot synthesis of substituted xanthenes.

A direct synthesis of substituted xanthenes from salicylaldehydes and cyclohexenones or tetralones has been developed. The reaction is catalysed by Lewis acids like scandium triflate and furnishes substituted xanthenes in good to excellent yields using either microwave or thermal heating. Microwave heating results in significantly shortened reaction times of 30 min and generally higher yields.