FluoroFusion: NHC-Catalyzed Nucleophilic Aromatic Substitution Reaction Unveils Functional Perfluorinated Diarylmethanones.

A mild, facile, and metal-free approach via the N-heterocyclic carbene-catalyzed SNAr reaction between aryl aldehydes with perfluoroarenes to obtain the coveted functional perfluorinated diarylmethanones is disclosed. This method accommodates a diverse substrate range and exhibits notable tolerance toward various functional groups. Our success in modifying biologically relevant molecules, crafting a fully fluorinated bioisosteric analogue of drug candidate D1, and highlighting the potential of these ketones as valuable electrolyte additives for lithium-ion batteries (LIBs) underscores the versatility of our methodology.

Pro-aromatic Dihydroquinazolinones - From Multigram Synthesis to Reagents for Gram-scale Metallaphotoredox Reactions.

Dihydroquinazolinone (DHQZ) has recently been harnessed as a ketone-derived pro-aromatic reagent extensively employed in (metalla)photoredox reactions as versatile group transfer agents. In this work, we outline a column chromatography-free protocol for the multigram-scale synthesis of pro-aromatic DHQZs as well as its use in a gram-scale nickel/photoredox dual-catalyzed cross-coupling in single-batch, photoflow, and simultaneous multiple smaller batches. While the single-batch approach leveraged moderate yields, a simple plug-flow photoreactor also exhibited amenable productivity (up to 45 % yield) despite the use of a heterogeneous base. Meanwhile, performing the metallaphotoredox-catalyzed reaction in multiple smaller batches in an improvised photoreactor facilitated high yields of up to 59 % and good reproducibility, implying a convenient alternative in the absence of photoflow setups.

Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization.

Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile synthesis of the elusive all-carbon quaternary-center-bearing azetidines. By adopting a well-orchestrated polar-radical relay strategy, ring strain release of bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB) can be harnessed for nickel-catalyzed Suzuki Csp2-Csp3 cross-coupling with commercially available boronic acids in broad scope (>50 examples), excellent functional group tolerance, and gram-scale utility. Preliminary mechanistic studies provided insights into the underlying mechanism, wherein the ring opening of ABB with a catalytic quantity of bromide accounts for the conversion of ABB into a redox-active azetidine, which subsequently engages in the cross-coupling reaction through a radical pathway. The synergistic bromide and nickel catalysis could intriguingly be derived from a single nickel source (NiBr2). Application of the method to modify natural products, biologically relevant molecules, and pharmaceuticals has been successfully achieved as well as the synthesis of melanocortin-1 receptor (MC-1R) agonist and vesicular acetylcholine transporter (VAChT) inhibitor analogues through bioisosteric replacements of piperidine with azetidine moieties, highlighting the potential of the method in drug optimization studies. Aside from the synthesis of azetidines, we demonstrate the ancillary utility of our nickel catalytic system toward the restricted Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic acids to construct all-carbon quaternary centers.

A protocol for the gram-scale synthesis of polyfluoroaryl sulfides via an SNAr step.

Polyfluoroaryl sulfide is one of the prevalent motifs ubiquitous in materials and pharmaceutical chemistry. We herein describe a simple yet efficient procedure for their synthesis from readily available thiols and polyfluoroarenes via an SNAr step. We detail specific steps for a gram-scale preparation of 2-((perfluoropyridin-4-yl)thio)benzo[d]thiazole 3 from mercaptobenzothiazole 1 and pentafluoropyridine 2. For complete details on the use and execution of this protocol, please refer to Liao et al. (2022).1.

Iterative synthesis of 1,3-polyboronic esters with high stereocontrol and application to the synthesis of bahamaolide A.

Polyketide natural products often contain common repeat motifs, for example, propionate, acetate and deoxypropionate, and so can be synthesized by iterative processes. We report here a highly efficient iterative strategy for the synthesis of polyacetates based on boronic ester homologation that does not require functional group manipulation between iterations. This process involves sequential asymmetric diboration of a terminal alkene, forming a 1,2-bis(boronic ester), followed by regio- and stereoselective homologation of the primary boronic ester with a butenyl metallated carbenoid to generate a 1,3-bis(boronic ester). Each transformation independently controls the stereochemical configuration, making the process highly versatile, and the sequence can be iterated prior to stereospecific oxidation of the 1,3-polyboronic ester to yield the 1,3-polyol. This methodology has been applied to a 14-step synthesis of the oxopolyene macrolide bahamaolide A, and the versatility of the 1,3-polyboronic esters has been demonstrated in various stereospecific transformations, leading to polyalkenes, -alkynes, -ketones and -aromatics with full stereocontrol.

Aza-Ortho-Quinone Methides as Reactive Intermediates: Generation and Utility in Contemporary Asymmetric Synthesis.

The aza-ortho-quinone methide (aza-o-QM) chemistry has overwhelmingly progressed in the past few decades. This review aims to integrate various transition metal-catalyzed and organocatalytic strategies in taming aza-o-QM intermediates, including the aza-ortho-vinylidene quinone methide (aza-o-VQM), aza-ortho-alkynyl quinone methide (aza-o-AQM), aza-para-quinone methide (aza-p-QM), and indole-based aza-o-QM analog. These transient species are often utilized for the direct and enantioselective synthesis of complex (hetero)polycyclic or fused-ring molecular scaffolds such as tetrahydroquinoline and indoline, among others, which are abundant in many natural products, bioactive compounds, and pharmaceuticals.

Desulfurative Ni-Catalyzed Reductive Cross-Coupling of Benzyl Mercaptans/Mercaptoacetates with Aryl Halides.

The C-S activation and sulfur removal from native thiols is challenging, which limits their application as feedstock materials in organic synthesis despite their natural abundance. Herein, we introduce a per-/polyfluoroaryl moiety, which serves as a redox-active scaffold, into sp3-hybridized thiols to activate the C-S bond. Using a Ni catalyst with MgBr2 as an additive, the S group can be removed to yield an aliphatic radical that can react with an aryl halide in a reductive cross-coupling.

Aromatization as an Impetus to Harness Ketones for Metallaphotoredox-Catalyzed Benzoylation/Benzylation of (Hetero)arenes.

Herein we report ketones as feedstock materials in radical cross-coupling reactions under Ni/photoredox dual catalysis. In this approach, simple condensation first converts ketones into prearomatic intermediates that then act as activated radical sources for cross-coupling with aryl halides. Our strategy enables the direct benzylation/benzoylation of (hetero)arenes under mild reaction conditions with high functional group tolerance.

Multiple Hydrogen-Bond Activation in Asymmetric Brønsted Acid Catalysis.

An efficient protocol for the asymmetric synthesis of chiral tetrahydroquinolines bearing multiple stereogenic centers by means of asymmetric Brønsted acid catalysis was developed. A chiral 1,1'-spirobiindane-7,7'-diol (SPINOL)-based N-triflylphosphoramide (NTPA) proved to be an effective Brønsted acid catalyst for the in situ generation of aza-ortho-quinone methides (aza-o-QMs) and their subsequent cycloaddition reaction with unactivated alkenes to provide the products with excellent diastereo- and enantioselectivities. In addition, DFT calculations provided insight into the activation mode and nature of the interactions between the N-triflylphosphoramide catalyst and the generated aza-o-QMs.

Ligand-Controlled Chemoselective C(acyl)-O Bond vs C(aryl)-C Bond Activation of Aromatic Esters in Nickel Catalyzed C(sp2)-C(sp3) Cross-Couplings.

A ligand-controlled and site-selective nickel catalyzed Suzuki-Miyaura cross-coupling reaction with aromatic esters and alkyl organoboron reagents as coupling partners was developed. This methodology provides a facile route for C(sp2)-C(sp3) bond formation in a straightforward fashion by successful suppression of the undesired ß-hydride elimination process. By simply switching the phosphorus ligand, the ester substrates are converted into the alkylated arenes and ketone products, respectively. The utility of this newly developed protocol was demonstrated by its wide substrate scope, broad functional group tolerance and application in the synthesis of key intermediates for the synthesis of bioactive compounds. DFT studies on the oxidative addition step helped rationalizing this intriguing reaction chemoselectivity: whereas nickel complexes with bidentate ligands favor the C(aryl)-C bond cleavage in the oxidative addition step leading to the alkylated product via a decarbonylative process, nickel complexes with monodentate phosphorus ligands favor activation of the C(acyl)-O bond, which later generates the ketone product.

Nickel-Catalyzed C-S Bond Formation via Decarbonylative Thioetherification of Esters, Amides and Intramolecular Recombination Fragment Coupling of Thioesters.

A nickel catalyzed cross-coupling protocol for the straightforward C-S bond formation has been developed. Various mercaptans and a wide range of ester and amide substrates bearing various substituents were tolerated in this process which afforded products in good to excellent yields. Furthermore, an intramolecular protocol for the synthesis of thioethers starting from thioesters has been developed. The utility of this protocol has been demonstrated in a new synthetic protocol of benzothiophene.

Nickel-Catalyzed C-CN Bond Formation via Decarbonylative Cyanation of Esters, Amides, and Intramolecular Recombination Fragment Coupling of Acyl Cyanides.

An efficient nickel-catalyzed decarbonylative cyanation reaction which allows the direct functional-group interconversion of readily available esters into the corresponding nitriles was developed. This reaction successfully offers access to structurally diverse nitriles with high efficiency and excellent functional-group tolerance and provides a good alternative to classical synthetic pathways from diazonium salts or organic halide compounds.

Amide to Alkyne Interconversion via a Nickel/Copper-Catalyzed Deamidative Cross-Coupling of Aryl and Alkenyl Amides.

A nickel-catalyzed deamidative cross-coupling reaction of amides with terminal alkynes as coupling partners was disclosed. This newly developed methodology allows the direct interconversion of amides to alkynes and enables a facile route for C(sp2)-C(sp) bond formation in a straightforward and mild fashion.

Catalytic Ester and Amide to Amine Interconversion: Nickel-Catalyzed Decarbonylative Amination of Esters and Amides by C-O and C-C Bond Activation.

An efficient nickel-catalyzed decarbonylative amination reaction of aryl and heteroaryl esters has been achieved for the first time. The new amination protocol allows the direct interconversion of esters and amides into the corresponding amines and represents a good alternative to classical rearrangements as well as cross coupling reactions.

Asymmetric Brønsted Acid Catalyzed Substitution of Diaryl Methanols with Thiols and Alcohols for the Synthesis of Chiral Thioethers and Ethers.

An enantioselective addition of thiols and alcohols to aza-ortho-quinone methides, starting from diaryl methanols, was developed. The asymmetric additions occur under mild reaction conditions in the presence of chiral phosphoric acids and furnish the corresponding adducts with excellent yields and enantioselectivities.

Asymmetric Brønsted Acid Catalyzed Synthesis of Triarylmethanes-Construction of Communesin and Spiroindoline Scaffolds.

Aza-ortho-quinone methides allow the straightforward asymmetric synthesis of natural-product-inspired indole scaffolds possessing a quaternary stereocenter. Our approach provides access to diverse communesin and spiroindoline derivatives with high enantioselectivity under mild reaction conditions. Predictable substitution patterns are found to be the key to our regiodivergent protocols.

Ortho-quinone methides as reactive intermediates in asymmetric brønsted Acid catalyzed cycloadditions with unactivated alkenes by exclusive activation of the electrophile.

An efficient method for the highly enantioselective synthesis of chiral chromanes bearing multiple stereogenic centers was developed. A chiral BINOL-based N-triflylphosphoramide proved to be an effective catalyst for the in situ generation of ortho-quinone methides (o-QMs) and their subsequent cycloaddition reaction with unactivated alkenes provided chromanes with excellent diastereo- and enantioselectivity.

Enantio- and diastereoselective access to distant stereocenters embedded within tetrahydroxanthenes: utilizing ortho-quinone methides as reactive intermediates in asymmetric Brønsted acid catalysis.

A protocol for the highly enantioselective synthesis of 9-substituted tetrahydroxanthenones by means of asymmetric Brønsted acid catalysis has been developed. A chiral binol-based N-triflyphosphoramide was found to promote the in situ generation of ortho-quinone methides and their subsequent reaction with 1,3-cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio- and diastereoselective Brønsted acid catalyzed desymmetrization of 5-monosubstituted 1,3-dicarbonyl substrates with ortho-quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.

Shedding light on Brønsted acid catalysis--a photocyclization-reduction reaction for the asymmetric synthesis of tetrahydroquinolines from aminochalcones in batch and flow.

A new asymmetric photocyclization-reduction cascade employing readily available aminochalcones has been developed. The reaction sequence has been achieved by unifying photochemistry and asymmetric Brønsted acid catalysis and involves photocyclization followed by Brønsted acid catalyzed enantioselective hydrogenation in batch and flow.

Shedding light on organocatalysis-light-assisted asymmetric ion-pair catalysis for the enantioselective hydrogenation of pyrylium ions.

A new light-driven asymmetric ion-pair catalysis procedure for the metal-free enantioselective hydrogenation of in situ generated pyrylium ions from readily available chalcones was developed (see scheme). The photo-assisted Brønsted acid catalyzed procedure has broad scope and allows, for the first time, access to valuable 4H-chromenes in good yields and with excellent enantioselectivities.