Axel Jacobi von Wangelin

Reductive Cross‐Coupling Reactions between Two Electrophiles

Reductive cross-electrophile coupling reactions have recently been developed to a versatile and sustainable synthetic tool for selective C-C bond formation. The employment of cheap and abundant electrophiles avoids the pre-formation and handling of organometallic reagents. In situ reductive coupling is effected in the presence of a transition-metal catalyst (Ni, Co, Pd, Fe) and a suitable metallic reductant (Mn, Zn, Mg). This Concept article assesses the current state of the art and summarizes recent protocols with various combinations of alkyl, alkenyl, allyl, and aryl reagents and highlights key mechanistic studies.

On the mechanism of photocatalytic reactions with eosin Y

Summary A combined spectroscopic, synthetic, and apparative study has allowed a more detailed mechanistic rationalization of several recently reported eosin Y-catalyzed aromatic substitutions at arenediazonium salts. The operation of rapid acid–base equilibria, direct photolysis pathways, and radical chain reactions has been discussed on the basis of pH, solvent polarity, lamp type, absorption properties, and quantum yields. Determination of the latter proved to be an especially valuable tool for the distinction between radical chain and photocatalytic reactions.

Oxidative N‐Heterocyclic Carbene Catalysis

Nucleophilic catalysis by N-heterocyclic carbenes (NHCs) has developed to a mature class of valuable carbon–carbon and carbon–heteroatom bond forming reactions over the past decade. Major effort has been devoted to the development of NHC-catalyzed acylations with carbonyl compounds, which can involve nucleophilic substitution at an activated carboxylate species or addition to an aldehyde to give an acylanion equivalent (Umpolung). Only recently, these modes of reactivity have been complemented with efficient protocols under oxidative conditions. Such pathways have opened a synthetically useful avenue to diverse carbonyl compounds and have been adopted for complex molecule synthesis. The prototype of oxidative NHC-catalyzed esterifications is embedded within the aerobic cellular respiration of mitochondria. The biological oxidative decarboxylation of pyruvate by a-keto acid dehydrogenases results in the formation of a formal thioester (acetylcoenzyme A). The enzyme uses two cofactors for this transformation: thiamine pyrophosphate, the conjugate acid of an N-heterocyclic carbene, and flavin adenine dinucleotide (FAD), a redox-active vitamin B2-ADP adduct. Since the 1970s, researchers have striven to adopt such oxidative esterification of aldehydes under biomimetic conditions employing thiazolium salts and various oxidation agents. Only recently, new protocols have been reported which demonstrate the synthetic value and versatility of NHC-catalyzed oxidative acylations (Scheme 1).

Metal-Free Carbonylations by Photoredox Catalysis†

The synthesis of benzoates from aryl electrophiles and carbon monoxide is a prime example of a transition-metal-catalyzed carbonylation reaction which is widely applied in research and industrial processes. Such reactions proceed in the presence of Pd or Ni catalysts, suitable ligands, and stoichiometric bases. We have developed an alternative procedure that is free of any metal, ligand, and base. The method involves a redox reaction driven by visible light and catalyzed by eosin Y which affords alkyl benzoates from arene diazonium salts, carbon monoxide, and alcohols under mild conditions. Tertiary esters can also be prepared in high yields. DFT calculations and radical trapping experiments support a catalytic photoredox pathway without the requirement for sacrificial redox partners.

Practical iron-catalyzed dehalogenation of aryl halides

An operationally simple iron-catalyzed hydrodehalogenation of aryl halides has been developed with 1 mol% Fe(acac)(3) and commercial t-BuMgCl as reductant. The mild reaction conditions (THF, 0 degrees C, 1.5 h) effect rapid chemoselective dehalogenation of (hetero)aryl halides (I, Br, Cl) and tolerate F, Cl, OR, SR, CN, CO(2)R, and vinyl groups.

Iron-Catalyzed Isomerizations of Olefins

Olefins are of prime importance as skeletal units and functional groups in a vast number of natural and synthetic molecules. Their steric rigidity and specific modes of reactivity have prompted the development of many synthetic methodologies for the generation and manipulation of olefins. Furthermore, olefins form the basis of modern petrochemistry and are direct precursors of most fine chemicals, materials, and pharmaceuticals. There are numerous efficient procedures for the generation or introduction of a double bond into organic molecules, such as condensation, elimination, dehydrogenation, olefination, cross-coupling, and metathesis reactions. The translocation of an already existing double bond is another strategy for the positioning of this functional group within a molecule, which is also realized on technical scales. Such structural modification is rather attractive for two reasons: 1) no skeletal C C bond formation, which might involve the addition of further substrates and the generation of by-products, is required; 2) many synthetic methods for the selective introduction of a terminal olefin moiety are known. Allylation reactions are a prime strategy for the synthesis of (terminal) 1-olefins. Upon selective one-carbon migration into the 2-position, an isomerization procedure can interlink the chemistry of allyl and vinyl groups without interference with distal parts of the molecule. Several protocols based on strong bases or palladium, ruthenium, iridium, platinum, and rhodium catalyst systems have been reported to selectively convey a terminal double bond into the 2-position. Most methods, however, require toxic or expensive transition metals, complex ligands, stoichiometric additives, or special reaction conditions (pressurized H2, heating, presence of strong bases). We wish to introduce a practical iron-catalyzed isomerization of terminal, internal, and (Z)-olefins under mild conditions (Scheme 1). Iron catalysts have recently been shown to be highly effective for cross-coupling, oxidation, hydrogenation, and other reactions. This emerging field of new methodologies under economically and environmentally attractive iron catalysis has neglected isomerizations so far. Isolated applications of photoactivated iron carbonyl complexes to the isomerization of olefins have been reported. We have recently observed olefin isomerization in the iron-catalyzed synthesis of allylbenzenes. In a preliminary study with allylbenzene (1) as model system, we ascertained that the observed olefin migration operates under iron catalysis in the presence of a reductant (Table 1). The optimized conditions (5 mol % [Fe(acac)3] , 25 mol % PhMgBr, 25 8C, 2 h) afforded 2 in quantitative yield as an E/Z mixture of 33/1 (Figure 1). Other transition metals showed little

Chlorostyrenes in Iron-Catalyzed Biaryl Coupling Reactions†

Palladiumand nickel-catalyzed cross-coupling reactions are among the most versatile methods for the assembly of biaryl compounds, which constitute important structural motifs of fine chemicals, materials, pharmaceuticals, and natural products. Suzuki–Miyaura reactions between arylboronic acids and aryl halides are carried out under especially mild conditions and exhibit high functional-group tolerance. 2] The constantly increasing world market price of palladium, the toxicity of nickel compounds, and the laborious synthesis of arylboronic acids are prompting the search for powerful alternatives, especially for industrial processes. The past years have witnessed the development of iron-catalyzed protocols, which boast high operational practicality and synthetic efficiency: the precatalysts are cheap and nontoxic iron salts; complex, air-sensitive ligands are not required; the mild reaction conditions tolerate various functional groups. To date, iron-catalyzed biaryl syntheses from aryl Grignard species and aryl (pseudo)halides proved rather unselective. Furthermore, only one protocol that largely suppressed the competing homocoupling has been reported for the effective utilization of cheap but sluggish aryl chlorides. This method requires a special precatalyst combination of iron(II) fluoride and a carbene ligand, the generation of the catalytically active species in a prior step, and elevated reaction temperatures. During our research program directed at iron-catalyzed biaryl syntheses, we became interested in the role of activating substituents. Electronegative heteroatom-based groups at the electrophile generally enhance its reactivity. Hydrocarbons, however, have received only little attention as activating substituents. Based upon the rich coordination chemistry of olefins with iron in low oxidation states, we postulated a novel mode of activation for olefin-substituted aryl chlorides. We assumed that sequential olefin coordination at the catalyst and haptotropic migration could effect C Cl bond activation of chlorostyrenes. Herein, we report an efficient iron-catalyzed biaryl synthesis by exploiting this unprecedented activation mechanism. The reaction of aryl Grignard species with chlorostyrenes proceeds under mild and practical reaction conditions in the presence of iron(III) tris(acetylacetonate) [Fe(acac)3] as precatalyst. Competitive reactions at the vinyl group (e.g., polymerization, carbometalation, and substitution) do not occur (Scheme 1). Our initial optimizations of the model reaction between ortho-chlorostyrene (1) and phenylmagnesium chloride (PhMgCl) are summarized in Table 1. Moderate yields of

Iron‐Catalyzed Reductive Aryl–Alkenyl Cross‐Coupling Reactions

Transition metal-catalyzed cross-coupling reactions constitute one of the most versatile methods for carbon–carbon bond formation. Apart from the established palladium and nickel catalyst systems, recent years have witnessed the development of new methods based upon economically and environmentally attractive iron catalysis. Iron-catalyzed cross-coupling reactions boast great operational simplicity, low costs, and high reactivity : The employed precatalysts are cheap and nontoxic iron salts; no addition of high-molecular-weight and airsensitive ligands is required; unactivated substrates (organochlorides) are reactive; the mild reaction conditions tolerate various functional groups. Metal-catalyzed cross-coupling methods, including Heck reactions, are also among the mostused systems for the synthesis of substituted styrenes, which are ubiquitous structural motifs in biological molecules and valuable intermediates of fine chemicals, agrochemicals, pharmaceuticals, and materials. 5] Whereas such reactions are dominated by palladium and nickel catalysts, only a handful of iron-catalyzed alkenylations of pre-formed arylmetal reagents have been reported, with mostly moderate yields of the crosscoupling product. The development of a direct crosscoupling between two sp electrophiles, an alkenyl halide and an aryl halide under in situ reductive conditions would shun the use of pre-formed organometallics but instead exploit the much cheaper and less hazardous organohalides. However, a stereoelectronic differentiation between both sp-hybridized electrophiles (aryl X, alkenyl Y) is key to a selective crosscoupling reaction. We recently demonstrated the concept of a sustainable domino iron catalysis in the context of direct sp sp cross-coupling reactions between aryl bromides and alkyl bromides via in situ formation of the organomagnesium species. Herein, we report our recent study of iron-catalyzed cross-coupling reactions of arylmagnesium bromides and alkenyl bromides and the direct reductive cross-coupling between aryl bromides and alkenyl bromides with the simple precatalyst FeCl3/TMEDA (TMEDA = N,N,N’,N’-tetramethylethylenediamine; Scheme 1). An initial investigation of electrophile/nucleophile combinations in the cross-coupling of phenyl and vinyl moieties resulted in the exclusive formation of styrene (3 a) from the reaction of phenylmagnesium bromide and vinyl bromide with a FeCl3/TMEDA (1:4) catalyst system. The electronically inverse reaction of bromobenzene and vinylmagnesium bromide led to no conversion under identical reaction conditions (Scheme 2). The high substrate selectivity is also reflected in the direct reductive cross-coupling of bromobenzene (1 a) and vinyl bromide (2 a). Unlike metal–halogen exchange based on expensive isopropylmagnesium chloride for the generation of the Grignard species, we rather resorted to a more sustainable strategy utilizing magnesium ribbons (Table 1).

Iron-Catalyzed Cross-Coupling of Alkenyl Acetates

Stable C-O linkages are generally unreactive in cross-coupling reactions which mostly employ more electrophilic halides or activated esters (triflates, tosylates). Acetates are cheap and easily accessible electrophiles but have not been used in cross-couplings because the strong C-O bond and high propensity to engage in unwanted acetylation and deprotonation. Reported herein is a selective iron-catalyzed cross-coupling of diverse alkenyl acetates, and it operates under mild reaction conditions (0 °C, 2 h) with a ligand-free catalyst (1-2 mol%).

Iron(0) Particles: Catalytic Hydrogenations and Spectroscopic Studies

Transition-metal-catalyzed hydrogenation reactions of alkenes and alkynes are among the most-important synthetic transformations; these reactions have found numerous lab-scale and technical applications in the synthesis of fine chemicals, pharmaceuticals, natural products, in the processing of vegetable oils and fatty acids, and in petrochemical conversion. Heterogeneous catalyst systems exhibit great thermal stability, low solvent dependence, and allow for their facile separation from the product mixture with extremely low product contamination. The most-prominent heterogeneous catalysts are based on nickel (Raneyor Urushibara nickel), palladium (Pd/charcoal ; Lindlar’s catalyst, Pd/CaCO3/poison), [4] and platinum (Adam’s catalyst, PtO2·H2O; Pt/charcoal). [5] For more than 100 years, metal-composite–oxide catalysts that contain iron have been used at high temperatures and high pressures in technical hydrogenation reactions, such as the Haber–Bosch process and the water–gas shift and Fischer–Tropsch reactions, whereas only a handful of iron catalysts have been developed for use in selective hydrogenation reactions under mild conditions. Recently, several groups have reported homogeneous iron-catalyzed reductions of carbonyl compounds, olefins, and alkynes. As part of our ongoing research that is directed at the utilization of cheap iron catalysts for the synthesis and manipulation of fine chemicals, we also became interested in the development of a practical and sustainable alternative to the established Raney-nickel-type catalysts. Herein, we report a hydrogenation procedure that combines the economic and environmental benefits of iron as a cheap and nontoxic metal catalyst with the operational simplicity of a heterogeneous process (Scheme 1). Hydrogenation reactions