Vilsmeier-Haack-Initiated Formylative Rearrangement of Spirodioxo-lan-5-ones into Functionalized 4,5,6,7-Tetrahydrobenzofurans.

Pharmaceutically relevant bicyclic furans can be synthesized in a single step from substituted dioxolan-5-ones by reacting with Vilsmeier-Haack reagents. These reagents are generated from POCl3 or PBr3 and DMF. The reaction cascade is mechanistically complex and involves deoxyhalogenation, iminomethylation, and electrophilic rearrangement steps, which are facilitated by the DMF solvent. The synthesis of hard-to-access 4,5,6,7-tetrahydrobenzofurans and substituted aliphatic furans is particularly useful. These compounds are potential isosteres of 2,3-dihydrobenzofuran pharmacophores and could be of interest for drug discovery.

Coupling of Aryl Chlorides with Lithium Nucleophiles Enabled by Molecularly Defined Alkynyllithium Palladium Catalysts.

Palladium-catalyzed cross-couplings of aryl chlorides usually call for bulky, electron-rich ligands such as phosphines or heterocyclic carbenes. We have now found that similarly powerful cross-coupling catalysts are obtained by the reaction of palladium salts with alkynyllithium reagents. The species initially formed in this process was characterized as a dilithium tetraalkinyl palladate complex. It catalyzes the coupling of aryl chlorides with the lithium salts of various terminal alkynes to give alkynyl arenes. The isolated Li-alkynyl-Pd complex also efficiently promotes the reaction of aryl, and allyl chlorides with (hetero)aryl-, alkyl-, and allyllithium compounds as well as lithium amides. None of these reactions proceeded in the presence of palladium salts alone. The preparative utility of this approach was demonstrated by the synthesis of 49 molecules, including pharmaceutically relevant compounds.

Manganese(I) Catalyzed ortho C-H Allylation of Benzoic Acids.

The 3d-metal catalyst Mn(CO)5 Br was found to efficiently promote ortho C-H allylations of arenecarboxylates in the presence of neocuproine as the ligand. Despite the simplicity of directing group and catalyst system, the selectivity goes well beyond the state-of-the-art in that mono-allylated products are obtained exclusively with high selectivities for the least hindered ortho-position. The directing group can optionally be removed by in situ decarboxylation, opening up a regioselective entry to allyl arenes. The preparative utility of the process and its othogonality to other approaches was demonstrated by 44 products with otherwise hard-to-access substitution patterns, including 3-bromo-allylbenzene, 3-allylbenzofuran, or 5-allyl-2-methylnitrobenzene.

C-H Fluoromethoxylation of Arenes by Photoredox Catalysis.

Redox-active N-(fluoromethoxy)benzotriazoles were made accessible from fluoroacetic acid and hydroxybenzotriazoles via electrodecarboxylative coupling. After alkylation, they become effective monofluoromethoxylation reagents, enabling the photocatalytic C-H functionalization of arenes. Thus, irradiation of 1-(OCH2 F)-3-Me-6-(CF3 )benzotriazolium triflate with blue LED light in the presence of [Ru(bpy)3 (PF6 )2 ] promotes the synthesis of diversely functionalized aryl monofluoromethyl ethers. This method allows the late-stage functionalization of biologically relevant structures without relying on ecologically problematic halofluorocarbons.

Enantioselective Synthesis of Arylglycines via Pd-Catalyzed Coupling of Schöllkopf Bis-Lactim Ethers with Aryl Chlorides.

Arylglycines are important pharmacophores present in several top-selling drugs. This compound class has now been made accessible from abundant aryl chlorides by a Pd-catalyzed Schöllkopf-type amino acid synthesis. In the presence of the catalyst methylnaphthyl(XPhos)-palladium bromide, the base lithium 2,2,6,6-tetramethylpyrrolidide and the additive ZnCl2 , tert-leucine-derived bis-lactim ethers were efficiently arylated at room temperature, reaching yields of 95 % and diastereoselectivities of 98 : 2. Hydrolysis gave the corresponding arylglycines in high enantiomeric excess.

Computer-Driven Development of Ylide Functionalized Phosphines for Palladium-Catalyzed Hiyama Couplings.

Palladium-catalyzed couplings of silicon enolates with aryl electrophiles are of great synthetic utility, but often limited to expensive bromide substrates. A comparative experimental study confirmed that none of the established ligand systems allows to couple inexpensive aryl chlorides with α-trimethylsilyl alkylnitriles. In contrast, ylide functionalized phosphines (YPhos) led to encouraging results. A statistical model was developed that correlates the reaction yields with ligand features. It was employed to predict catalyst structures with superior performance. With this cheminformatics approach, YPhos ligands were tailored specifically to the demands of Hiyama couplings. The newly synthesized ligands displayed record-setting activities, enabling the elusive coupling of aryl chlorides with α-trimethylsilyl alkyl nitriles. The preparative utility of the catalyst system was demonstrated by the synthesis of pharmaceutically meaningful α-aryl alkylnitriles, α-arylcarbonyls and biaryls.

Carboxylation of Acetylene without Salt Waste: Green Synthesis of C4 Chemicals Enabled by a CO2 -Pressure Induced Acidity Switch.

The inherent formation of salt waste in C-H carboxylations is a key obstacle precluding the utilization of CO2 as C1 building block in the industrial synthesis of base chemicals. This challenge is addressed in a circular process for the production of the C4 base chemical dimethyl succinate from CO2 and acetylene. At moderate CO2 pressures, acetylene is doubly carboxylated in the presence of cesium carbonate. Hydrogenation of the C-C triple bond stabilizes the product against decarboxylation. By increasing the CO2 pressure to 70 bar, the medium is reversibly acidified, allowing an esterification of the succinate salt with methanol. The cesium base and the hydrogenation catalyst are regenerated and can be reused. This provides the proof of concept for a salt-free route to C4 chemicals from biogas (CH4 /CO2 ). The origin of this reversible acidity switch and the critical roles of the cesium base and the NMP/MeOH solvents were elucidated by thermodynamic modeling.

Photochemical Sandmeyer-type Halogenation of Arenediazonium Salts.

Trihalide salts were found to efficiently promote photochemical dediazotizing halogenations of diazonium salts. In contrast to classical Sandmeyer reactions, no metal catalysts are required to achieve high yields and outstanding selectivities for halogenation over competing hydridodediazotization. Convenient protocols are disclosed for synthetically meaningful brominations, iodinations, and chlorinations of diversely functionalized derivatives.

Palladium-Catalyzed para-C-H Arylation of Anilines with Aromatic Halides.

Controlling regioselectivity in C-H functionalizations is a key challenge in chemical method development. In arenes, functionalizations are most difficult to direct towards the C-H group furthest away from a substituent, in its para position. We herein demonstrate how the para-C-H arylation of anilines with non-activated aryl halides, elusive to date, is achieved by a base-assisted "metalla-tautomerism" approach. A proton is abstracted from the aniline substrate and replaced by an arylpalladium species, generated from the aryl halide coupling partner. In this step, the palladium is directed away from the N- to the tautomeric para-C-H position by a large phosphine ligand combined with a triphenylmethyl shielding group. The triphenylmethyl group is easily installed and removed, and can be recycled.

Concentrated Aqueous Peroxodicarbonate: Efficient Electrosyn- thesis and Use as Oxidizer in Epoxidations, S-, and N-Oxidations.

Peroxodicarbonates are of substantial interest as potentially powerful and sustainable oxidizers but have so far been accessible only in low concentrations with unsatisfactory energy efficiency. Concentrated (> 0.9 mol L-1 ) peroxodicarbonate solutions have now been made accessible by the electrolysis of aqueous K2 CO3 /Na2 CO3 /KHCO3 solutions at high current density of 3.33 A cm-2 in an efficiently cooled circular flow reactor equipped with a boron-doped diamond anode and a stainless-steel cathode. Their synthetic potential as platform oxidizers was clearly demonstrated in transformations including sulfoxidation, N-oxidation, and epoxidation.

Isomerization of Functionalized Olefins by Using the Dinuclear Catalyst [PdI (µ-Br)(Pt Bu3 )]2 : A Mechanistic Study.

In a combined experimental and computational study, the isomerization activity of the dinuclear palladium(I) complex [PdI (µ-Br)(Pt Bu3 )]2 towards allyl arenes, esters, amides, ethers, and alcohols has been investigated. The calculated energy profiles for catalyst activation for two alternative dinuclear and mononuclear catalytic cycles, and for catalyst deactivation are in good agreement with the experimental results. Comparison of experimentally observed E/Z ratios at incomplete conversion with calculated kinetic selectivities revealed that a substantial amount of product must form via the dinuclear pathway, in which the isomerization is promoted cooperatively by two palladium centers. The dissociation barrier towards mononuclear Pd species is relatively high, and once the catalyst enters the energetically more favorable mononuclear pathway, only a low barrier has to be overcome towards irreversible deactivation.

Halogen-Bridged Methylnaphthyl Palladium Dimers as Versatile Catalyst Precursors in Coupling Reactions.

Halogen-bridged methylnaphthyl (MeNAP) palladium dimers are presented as multipurpose Pd-precursors, ideally suited for catalytic method development and preparative organic synthesis. By simply mixing with phosphine or carbene ligands, they are in situ converted into well-defined monoligated complexes. Their catalytic performance was benchmarked against state-of-the-art systems in challenging Buchwald-Hartwig, Heck, Suzuki and Negishi couplings, and ketone arylations. Their use enabled record-setting activities, beyond those achievable by optimization of the ligand alone. The MeNAP catalysts permit syntheses of tetra-ortho-substituted arenes and bulky anilines in near-quantitative yields at room temperature, allow mono-arylations of small ketones, and enable so far elusive cross-couplings of secondary alkyl boronic acids with aryl chlorides.

Coupling of Reformatsky Reagents with Aryl Chlorides Enabled by Ylide-Functionalized Phosphine Ligands.

The coupling of aryl chlorides with Reformatsky reagents is a desirable strategy for the construction of α-aryl esters but has so far been substantially limited in the substrate scope due to many challenges posed by various possible side reactions. This limitation has now been overcome by the tailoring of ylide-functionalized phosphines to fit the requirements of Negishi couplings. Record-setting activities were achieved in palladium-catalyzed arylations of organozinc reagents with aryl electrophiles using a cyclohexyl-YPhos ligand bearing an ortho-tolyl-substituent in the backbone. This highly electron-rich, bulky ligand enables the use of aryl chlorides in room temperature couplings of Reformatsky reagents. The reaction scope covers diversely functionalized arylacetic and arylpropionic acid derivatives. Aryl bromides and chlorides can be converted selectively over triflate electrophiles, which permits consecutive coupling strategies.

Pd-Catalyzed Synthesis of Vinyl Arenes from Aryl Halides and Acrylic Acid.

Acrylic acid is presented as an inexpensive, non-volatile vinylating agent in a palladium-catalyzed decarboxylative vinylation of aryl halides. The reaction proceeds through a Heck reaction of acrylic acid, immediately followed by protodecarboxylation of the cinnamic acid intermediate. The use of the carboxylate group as a deciduous directing group ensures high selectivity for monoarylated products. The vinylation process is generally applicable to diversely substituted substrates. Its utility is shown by the synthesis of drug-like molecules and the gram-scale preparation of key intermediates in drug synthesis.

Isomerizing Olefin Metathesis.

Isomerizing olefin metathesis is currently undergoing a transformation from laboratory curiosity to powerful synthetic concept at the heart of orthogonal tandem catalysis. In this process, an isomerization catalyst continuously moves double bonds along carbon chains, while a metathesis catalyst scrambles the residues at the C-C double bonds. This cooperative action of two catalysts can be used to access single, defined products from a complex mixture of compounds. Alternatively, it enables the transformation of uniform starting materials into complex product blends with defined, tunable properties. This concept article highlights recent developments and potential applications of this fascinating reaction concept.

Enantio- and Diastereoswitchable C-H Arylation of Methylene Groups in Cycloalkanes.

A complementary set of chiral N,N-ligands enables the Pd-catalyzed ß-C-H arylation of unbiased internal methylene groups in good yield and with high levels of enantio- and diastereoinduction. Both the dia- and enantioselectivity can be reversed, thus allowing the selective arylation of any of the four ß-C-H bonds in cycloalkanecarboxamides of various ring sizes. The method is applicable to a broad range of aryl iodides with electron-withdrawing and -donating substituents in the o-, m-, or p-position.

Decarboxylative ipso Amination of Activated Benzoic Acids.

In the presence of a bimetallic Pd/Cu system with 1,10-phenanthroline as the ligand and either air or N-methylmorpholine N-oxide as the oxidant, electron-deficient benzoic acids undergo oxidative decarboxylative coupling with unprotected amines. This operationally simple aniline synthesis is widely applicable with respect to the amine and gives good yields, even on multigram scale. The orthogonality of this reaction to other Pd-catalyzed cross-couplings allows the concise synthesis of multisubstituted arenes by sequential C-C, C-Cl, and C-N functionalizations. Mechanistic investigations suggest the intermediacy of a hypervalent Pd species.

Rhodium-Catalyzed Annelation of Benzoic Acids with α,ß-Unsaturated Ketones with Cleavage of C-H, CO-OH, and C-C Bonds.

In the presence of a [Cp*RhCl2 ]2 catalyst, the Lewis acid In(OTf)3 , and the mild base Na2 CO3 , aromatic carboxylates and α,ß-unsaturated ketones undergo a unique hydroarylation/Claisen/retro-Claisen process to give the corresponding indanones. In this carboxylate-directed ortho-C-H annelation, the C-COR bond of the ketone and the CO-OH group of the aromatic carboxylate are cleaved, and the hydroxy group is transferred from the aromatic to the aliphatic acyl residue. This reactivity is synthetically useful, particularly when starting from cyclic ketones, which are converted into indanones bearing aliphatic carboxylate side chains, thus greatly increasing the molecular complexity of aromatic carboxylates in a single step.

A Highly Active Ylide-Functionalized Phosphine for Palladium-Catalyzed Aminations of Aryl Chlorides.

Ylide-functionalized phosphine ligands (YPhos) were rationally designed to fit the requirements of Buchwald-Hartwig aminations at room temperature. This ligand class combines a strong electron-donating ability comparable to NHC ligands with high steric demand similar to biaryl phosphines. The active Pd species are stabilized by agostic C-H⋅⋅⋅Pd rather than by Pd-arene interactions. The practical advantage of YPhos ligands arises from their easy and scalable synthesis from widely available, inexpensive starting materials. Benchmark studies showed that YPhos-Pd complexes are superior to the best-known phosphine ligands in room-temperature aminations of aryl chlorides. The utility of the catalysts was demonstrated by the synthesis of various arylamines in high yields within short reaction times.

Regioselective C-H Alkylation via Carboxylate-Directed Hydroarylation in Water.

In the presence of catalytic [RuCl2 (p-cym)]2 and using Li3 PO4 as the base, benzoic acids react with olefins in water to afford the corresponding 2-alkylbenzoic acids in moderate to excellent yields. This C-H alkylation process is generally applicable to diversely substituted electron-rich and electron-deficient benzoic acids, along with α,ß-unsaturated olefins including unprotected acrylic acid. The widely available carboxylate directing group can be removed or utilized for further derivatization. Mechanistic investigations revealed that the transformation proceeds via a ruthenacycle intermediate.