Armido Studer

A “Renaissance” in Radical Trifluoromethylation

This Minireview highlights recent developments in radical trifluoromethylation reactions. The trifluoromethyl group belongs to the privileged moieties in medicinal chemistry. Many drugs and drug candidates contain a trifluoromethyl substituent. Also in agrochemicals, the CF(3) moiety often appears. The present article addresses the radical trifluoromethylation of alkenes and arenes mainly focussing on recent achievements. However, important earlier work in this field is also covered.

Nitroxides: Applications in Synthesis and in Polymer Chemistry

This Review describes the application of nitroxides to synthesis and polymer chemistry. The synthesis and physical properties of nitroxides are discussed first. The largest section focuses on their application as stoichiometric and catalytic oxidants in organic synthesis. The oxidation of alcohols and carbanions, as well as oxidative C-C bond-forming reactions are presented along with other typical oxidative transformations. A section is also dedicated to the extensive use of nitroxides as trapping reagents for C-centered radicals in radical chemistry. Alkoxyamines derived from nitroxides are shown to be highly useful precursors of C-centered radicals in synthesis and also in polymer chemistry. The last section discusses the basics of nitroxide-mediated radical polymerization (NMP) and also highlights new developments in the synthesis of complex polymer architectures.

NHC Catalyzed Oxidations of Aldehydes to Esters: Chemoselective Acylation of Alcohols in Presence of Amines

Not just one but two carbenes of the same structure act cooperatively in oxidative acylations of alcohols with aldehydes by using a readily available cheap organic oxidant. Alcohols are selectively acylated in the presence of amines by cooperative carbene catalysis. Quantum chemical calculations support the suggested mechanism.

Catalysis with N-Heterocyclic Carbenes under Oxidative Conditions

This Concept article discusses the potential of oxidative carbene catalysis in synthesis and comprehensively covers pioneering studies as well as recent developments. Oxidative carbene catalysis can be conducted by using inorganic and organic oxidants. Applications in cascade processes, in enantioselective catalysis, and also in natural product synthesis are discussed.

The persistent radical effect in organic synthesis.

The persistent radical effect (PRE) is a principle that explains the highly selective cross-coupling between a persistent and a transient radical when both species are formed at equal rates. In this paper, the concept of the PRE is briefly discussed. Applications of the PRE in different reactions such as Co-mediated radical addition and cyclization reactions, Kharasch reactions catalyzed by transition metals, the Barton reaction, and our nitroxide-mediated tin-free radical cyclizations are presented. Some future perspectives for the PRE in organic synthesis are also provided.

6‐Trifluoromethyl‐Phenanthridines through Radical Trifluoromethylation of Isonitriles

The trifluoromethyl group can be found in many drugs or drug candidates. Chemical and physical properties of biologically active compounds are altered upon incorporation of the CF3 group. The higher solubility and lipophilicity exerted by the fluorinated methyl group lead to better membrane permeability and increased bioavailability. Importantly, because of the higher resistance toward oxidative degradation, fluorinated compounds generally have higher metabolic stability. Therefore, development of new methods for C CF3 bond formation has caught great attention from the synthetic community during the past few years and different methods for the trifluoromethylation of arenes have been developed. Transition-metal-catalyzed and radical aromatic trifluoromethylation have been studied intensively (Scheme 1).

NHC‐Catalyzed Michael Addition to α,β‐Unsaturated Aldehydes by Redox Activation

The formation of C C bonds undoubtedly belongs to the most important transformations in organic chemistry, and Michael reactions are important examples thereof. Two strategies have mainly been followed for the activation of Michael acceptors to conduct conjugate addition reactions: a) activation by using Lewis or Brønsted acids and b) activation by iminium ion generation. It has been shown independently by Bode and Glorius that a,bunsaturated aldehydes 1 react with N-heterocyclic carbenes (NHCs) 2 to umpoled intermediates of type A, which can then react as homoenolates at the b position with various electrophiles to give product B (Scheme 1).

Oxidative Amidation and Azidation of Aldehydes by NHC Catalysis

N-heterocyclic carbene catalyzed oxidative amidations of various aldehydes to the corresponding hexafluoroisopropylesters by using the readily available organic oxidant A are described. The hexafluoroisopropylesters prepared in situ are shown to be highly useful active esters for amide bond formation. In addition, oxidative azidation of aldehydes is presented. These mild organocatalytic processes do not use any transition metal.

Biomimetic carbene-catalyzed oxidations of aldehydes using TEMPO.

Pyruvate ferredoxin oxidoreductase (PFOR), which catalyzes the oxidative decarboxylation of pyruvate to form acetyl-CoA and CO2, belongs to the family of 2-keto acid oxidoreductases. This CoA-dependent enzyme uses thiamine pyrophosphate (TPP) as an additional cofactor. The anaerobic decarboxylation is a reversible process, and the two electrons obtained during one turnover are transferred to ferredoxine via [Fe4S4] clusters. [1] The initial steps of the oxidative decarboxylation resemble those of the aerobic TPP-dependent 2-oxoacid dehydrogenases. Pyruvate reacts with A to form B after proton transfer, and B subsequently undergoes CO2 elimination to generate C (Scheme 1). Electron transfer to a [Fe4S4] cluster leads to radical cation D. Although intensive studies (X-ray and EPR) have been conducted on D, the structure of the radical cation is still under debate. Renewed electron transfer in the presence of CoASH eventually leads to CoASAc. In aerobic organisms lacking the [Fe4S4] clusters, C reacts with the dithiolane ring of a lipoyl group in a formal twoelectron transfer to an acetyl lipoamide thioester intermediate, which is further transformed in the presence of CoASH using another enzyme to CoASAc. The liberated dithiol is eventually reoxidized to the cyclic disulfide by a FADdependent dihydrolipoyl dehydrogenase. It is known in synthesis that reaction of aldehydes with thiazolium carbenes leads to intermediates of type C which react as “umpoled” nucleophiles with aromatic aldehydes (benzoin condensation) or with electron-poor olefins (Stetter reaction). Recently, N-heterocyclic carbene (NHC) catalyzed transformations have gained increasing attention. However, these investigations have focused on ionic processes. Guided by PFOR we planned to oxidize enamines of type C by organic single-electron transfer (SET) oxidants. The process would represent a biomimetic transition-metalfree organocatalytic oxidation of an aldehyde. As the oxidant we used 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO), which has been used successfully by our group in transition-metal-mediated reactions and in various radical processes. Hence, the oxidizing [Fe4S4] clusters in PFOR can be replaced by two oxidizing TEMPO units [Eq. (1)].

Oxidative Biaryl Coupling of Thiophenes and Thiazoles with Arylboronic Acids through Palladium Catalysis: Otherwise Difficult C4‐Selective CH Arylation Enabled by Boronic Acids

Heteroarenes equipped with aryl groups (heterobiaryls) are often found in biologically active compounds, organic materials, and pharmaceuticals. In recent years, the direct C H arylation of heteroarenes catalyzed by a transition-metal complex 2] has emerged as a practical alternative to the wellestablished Pd-catalyzed cross-coupling reactions. Although tremendous efforts in the synthetic community including our groups have culminated in a wealth of useful and highly active catalysts, considerable room remains for further investigations. In particular, the development of a unique catalytic system that can preferentially activate and arylate an otherwise less reactive C H bond on heteroarenes is critically important from both scientific and practical points of view. For example, the Pd-catalyzed arylation of C H bonds of thiophenes with haloarenes is known to occur preferentially at the positions a to the sulfur atom (C2 and/or C5) following the typical reactivity profile of the thiophene ring (Scheme 1, top reaction). 7] Except for very rare cases, 8] selective and preferential arylation at the positions b to the sulfur atom (C3 and/or C4) does not take place. This is also true for the arylation of thiazoles, and a catalytic system that can preferentially arylate the least reactive C4 positions has not been forthcoming. We herein report that the Pd-catalyzed oxidative C H arylation of thiophenes and thiazoles with arylboronic acids manifests the otherwise difficult C4 regioselectivity (Scheme 1, bottom reaction). The present finding is significant not only because the regioselective outcome is complementary to that of the arylation using haloarenes, but also because it demonstrates the remarkable mechanistic difference between these two seemingly related Pd-catalyzed direct arylation processes. In early experiments, we found that the C H arylation of 2-ethylthiophene (1a) with phenylboronic acid (2a) took place in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO), Pd(OAc)2, and 2,2’-bipyridyl (bipy) in 1,2-dichloroethane (DCE) at 80 8C (Table 1, entry 1). Very surprisingly, we identified 2-ethyl-4-phenylthiophene (3aa) to be the sole coupling product under these conditions (69% yield). The corresponding C5-phenylation product (4aa) was not identified. Based on these promising initial results we decided to further optimize the reaction conditions (Table 1). After we had found that the bipy is necessary for the reaction to occur (entry 2), we screened various nitrogen-based bidentate ligands such as bipy derivatives (L1–L3), phenanthrolines (L4–L6), and TMEDA (L7) in the reaction of 1a with 2a (entries 3–9). Although L4 and L6 were found to be equally effective ligands in terms of yield and regioselectivity, we selected bipy as the standard ligand for subsequent experiments in view of its efficiency, cost, and simplicity. With a,a,atrifluorotoluene as a solvent, a slightly higher yield (76 %) was obtained (entry 10) and the reaction also proceeded at lower temperatures, remarkably even at room temperature (entry 11). Replacing TEMPO with other oxidants such as p-benzoquinone, (diacetoxyiodo)benzene, and copper(II) chloride resulted in a much lower reaction efficiency (entries 12–14). Higher concentrations of 1a in a,a,atrifluorotoluene resulted in higher yields while the high regioselectivity was maintained (entries 15 and 16). Reducing the catalyst loading to 5 or 2 mol% Pd(OAc)2 led to a slight Scheme 1. Reagent-controlled regiodivergency in the Pd-catalyzed C H arylation of thiophenes and thiazoles.