ChemDigest

Dibenzofuran and its derivatives are ubiquitous and important medicinal and natural products. Many contain electron-donating substituents. Herein, we report a Pd-catalysed C−H functionalisation protocol that works with electron-rich arenes. We use tetrabutylammonium acetate (NBu₄OAc), which we suspect can act as base and ligand, rendering this protocol a simple and efficient route to dibenzofurans.

Abstract

Dibenzofuran and its derivatives are ubiquitous and important medicinal and natural products. Many contain electron-rich aryl rings. Forming the key intramolecular Ar−Ar bond using traditional cross-coupling is difficult. The C−H functionalisation (C−H activation) approach is, in principle, far more useful. However, we previously found that the well-established conditions, which promote C−H functionalisation through Concerted Metalation-Deprotonation (CMD), proved unsatisfactory. Herein, we report a Pd-catalysed C−H functionalisation protocol that works with electron-rich arenes. We use tetrabutylammonium acetate (NBu₄OAc), which we suspect can act as base, ligand and solvent, rendering this protocol a simple and efficient route to electron-rich dibenzofurans.

Tau be or not tau be. A variety of fluorescent thiophene-vinylene-based ligands was synthesized. Ligands with specific chemical composition displayed selectivity towards distinct protein aggregates in tissue sections with Alzheimer’s disease pathology and distinct heterocyclic moieties governed the selectivity of the ligand towards Aβ or tau pathology. We foresee that these findings will aid in designing ligands towards disease-associated protein aggregates.

Abstract

Distinct aggregated proteins are correlated with numerous neurodegenerative diseases and the development of ligands that selectively detect these pathological hallmarks is vital. Recently, the synthesis of thiophene-based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs), that could be utilized for selective assignment of tau pathology in brain tissue with Alzheimer’s disease (AD) pathology, was reported. Herein, we investigate the ability of these ligands to selectively distinguish tau deposits from aggregated amyloid-β (Aβ), the second AD associated pathological hallmark, when replacing the terminal thiophene moiety with other heterocyclic motifs. The selectivity for tau pathology was reduced when introducing specific heterocyclic motifs, verifying that specific molecular interactions between the ligands and the aggregates are necessary for selective detection of tau deposits. In addition, ligands having certain heterocyclic moieties attached to the central thiophene-vinylene building block displayed selectivity to aggregated Aβ pathology. Our findings provide chemical insights for the development of ligands that can distinguish between aggregated proteinaceous species consisting of different proteins and might also aid in creating novel agents for clinical imaging of tau pathology in AD.

In this work, we explore how adding a catalytic amount of an NC-type ligand improves ketone-directed ortho C−H arylation, whereas a full equivalent shuts down the transformation. Increased catalytic activity stems from the formation of a cyclometallated complex containing the NC-type ligand to provide an intermediate which accelerates the ortho-arylation of the ketone substrate.

Abstract

Herein, we report a ruthenium-catalyzed ketone directed ortho-arylation wherein the addition of a bidentate NC-type ligand, most effectively 2-(o-tolyl) pyridine, significantly enhances the C−H arylation reaction. Various aryl-alkyl ketones, including cyclic, aliphatic, and heterocyclic ones, are competent substrates, and arylboronic acid esters were used as aryl sources. However, substitution with OMe and CF₃ in the aromatic ring of the ketone substrates is not tolerated, while such residues on the benzoic ester are possible. Notably, this study provides valuable insights into ketone-directed ortho arylation in the presence of 2-(o-tolyl) pyridine and adds additional options for catalyst and ligand optimization in ruthenium-catalyzed C−H functionalization.

In this work, we have described an efficient protocol for the photoinduced defluorocarboxylation of α-trifluoromethylstyrene using formate as the CO₂ radical anion precursor, which successfully yields a wide variety of gem-difluorovinylacetic acids with excellent functional group tolerance.

Abstract

Herein, we report an efficient protocol in which formate is used as a precursor of the CO₂ radical anion for the photoinduced defluorocarboxylation of α-trifluoromethylstyrene. A wide range of gem-difluorovinylacetic acids bearing a variety of functional groups were successfully obtained in the absence of metal catalysts. The synthetic value of this protocol was highlighted by successful gram-scale synthesis and late-stage modification for complex biologically active molecules. This protocol provides a complementary method that extends the range of currently available methodologies for accessing the structurally versatile gem-difluoroalkenes.

N-heterocyclic olefin (NHO) is known as a highly electron-donative ligand, but its application to metal catalysts has rarely been studied. In this study, a well-defined NHO ligated-Pd catalyst was developed. N-substituents on NHO ligand affected the catalytic performance, and the addition of a phosphine co-ligand, in particular [2-(MeO)C₆H₄]₃P was effective to enhance the activity.

Abstract

N-heterocyclic olefin (NHO) is known as a highly electron-donative ligand, but its application to metal catalysts has rarely been studied. In this study, we synthesized 2-methyleneimidazolidine ligands equipped with a bicyclic frameworks with the goal of developing a NHO-ligated Pd catalyst. These synthesized [(NHO)PdCl(μ-Cl)]₂ complexes had a phosphine co-ligand that proved effective as a catalyst for Suzuki-Miyaura coupling at ambient temperature. By optimizing the N-substituents of NHO ligands and a phosphine co-ligand, we developed a [(NHO)Pd{[2-(CH₃O)C₆H₄]₃P}Cl₂] complex as a catalyst that shows good catalytic activity.

Newly developed rigid-featured chiral Fu-2NO ligands possesses two pyrroloimidazolone-based N-oxides as non-flat chiral walls, and afforded the opportunity for fine-tuning the ligand’s electronic and conformational properties by judicious choice of the substituent in the nonligating nitrogen atom.

Abstract

To expand the chemical space of chiral N-oxides and chiral furan-containing ligands, herein we designed and synthesized a new class of rigid-featured tertiary amine-derived C₂-symmetric chiral furan-N,N′-dioxide (Fu-2NO) ligands from optically pure l-prolinamides/hydroxylprolinamides in operationally simple two steps and up to 57 % overall yield. The newly developed rigid-featured chiral Fu-2NO ligands possesses two pyrroloimidazolone-based N-oxides as non-flat chiral walls, and afforded the opportunity for fine-tuning the ligand electronic and conformational properties by judicious choice of the substituent in the nonligating nitrogen atom. More importantly, The Fu-2NO ligands can tolerate air and moisture such that no special handling is needed for their storage, and can be applied in the Ni(II)-catalyzed asymmetric Friedel-Crafts alkylation reaction of indole.

Utilizing the nitrogen-substituted donor-acceptor cyclopropane, enantiospecific total syntheses of (−)-hyacinthacine A₁⋅HCl and (+)-hyacinthacine A₁⋅HCl were achieved. The key reactions were highly stereo- and regioselective intramolecular cyclopropanation with rhodium(II) acetate and regioselective ring opening of nitrogen-substituted D−A cyclopropanes.

Abstract

A concise and efficient enantiospecific total synthesis of (−)-hyacinthacine A₁ and (+)-hyacinthacine A₁ was achieved from commercially available starting material L-pyroglutamic acid and D-glutamic acid, respectively. For the synthesis of this trihydroxylated pyrrolizidine ring, we employed the nitrogen-substituted donor-acceptor cyclopropane as a key intermediate. The synthetic approach relies on two crucial steps, highly stereo- and regioselective intramolecular cyclopropanation with Rh₂(OAc)₄ and regioselective ring opening of a nitrogen-substituted donor-acceptor cyclopropane.

Mn-mediated hydroxyphosphonylation of α-CF₃-styrenes with H-phosphonates and transition-metal-free hydroxyphosphinylation of α-CF₃-styrenes with H-phosphine oxides with the assistance of air were developed. A variety of β-hydroxy-β-CF₃-phosphonates and β-hydroxy-β-CF₃-phosphine oxides were synthesized in moderate to good yields.

Abstract

Efficient synthesis of β-hydroxy-β-CF₃-phosphonates and β-hydroxy-β-CF₃-phosphine oxides by Mn-mediated or transition-metal-free hydroxyphosphorylation of α-trifluoromethy)styrenes with H-phosphonates or H-phosphine oxides with the assistance of air, respectively, was described.

Previously, 6,6-dimethoxy-6,7-dihydrobenzocyclohepten-5-ones (“ketoketals”) gained by ring-closing metatheses (“RCMs”) gave 6-hydroxybenzocyclohepten-5-ones (“benzotropolones”) by hydrolyses with 10 equiv. of hot TsOH. Now, an RCM-based ketoketal allowed to reach the benzotropolone aurantricholone by total synthesis for the second time and to avoid a forcing hydrolysis. Another key to success was establishing the pulvinone(−like) motifs by our recently developed Suzuki strategy.

Abstract

Our first total synthesis of aurantricholone established its benzotropolone core by the ring-enlargement of a tetralone. Here we describe another total synthesis of aurantricholone. It reaches the benzotropolone core from a known olefin metathesis product via an equally known dibromide, both of which contain a ketoketal moiety. The next transformation – step 9 overall – engaged this motif in a β-elimination of ROH rather than in a hydrolysis under the forcing acidic conditions indispensable in all prior benzotropolone preparations from such an intermediate. In step 10, the C _sp2−Br bonds of the elimination product underwent two doubly Z-selective Suzuki couplings with a boronylated O-methyl 4-methylidenetetronate. This gave penta(O-methyl)aurantricholone. Its NMR shifts matched essentially those of a derivative of natural aurantricholone by Steglich et al. Three O−Me bonds were cleaved with BBr₃/CH₂Cl₂ (step 11) and two O−Me bonds with LiBr/DMF (step 12). A 1 : 3 co-crystal of aurantricholone and DMSO allowed for an X-ray structure analysis.

Reaction of 2,5-dibromothiophene dioxide with two equivalents of tetracyclone yields a heptaphenyl triphenylene, presumably by double Diels-Alder addition followed by fragmentation and rearrangement of the resulting radicals.

Abstract

In attempts to make octaphenyldibenzofuran (7) and octaphenyldibenzothiophene (8), 2,5-dibromofuran (4) and 2,5-dibromothiophene (5), respectively, were heated with tetracyclone (2) under forcing conditions, but only single addition products, such as 2-bromo-4,5,6,7-tetraphenylbenzofuran (10) and 2-bromo-4,5,6,7-tetraphenylbenzothiophene (12) were observed. However, when 2,5-dibromothiophene-1,1-dioxide (6) was heated with tetracyclone, the chief product was 1,2,3,4,6,7,8-heptaphenyltriphenylene (14). Similarly, when compound 6 was heated with acecyclone (15), the product was 11,18,20-triphenyldiacenaphtho[a,h]triphenylene (16). Both 14 and 16 have been characterized by X-ray crystallography. They are proposed to form from double Diels-Alder addition products of the cyclopentadienones by extrusion of sulfur dioxide and rearrangement of the resulting radicals.

A direct protocol for the facile construction of axially chiral iodobenzocarbazole derivatives via the catalytic asymmetric iodocyclization of indole moiety linked alkynes, using stereogenic-at-cobalt(III)-complex as the catalyst, has been developed. A range of versatile axially chiral iodobenzocarbazoles were obtained with up to 98 % ee under mild conditions.

Abstract

A new synthetic approach to novel axially chiral iodobenzocarbazole derivatives based on the highly enantioselective intramolecular iodoarylation of linked alkyne-indole systems was developed by using the versatile chiral catalyst, stereogenic-at-cobalt(III)-complex, through an axially chiral iodinated vinylidene o-quinone methide (IVQM) intermediate. This protocol provides 21 examples in excellent yields with good to high enantioselectivities (up to 96 % yield, 98 % ee). Furthermore, the introduced iodine atoms can easily be converted into other functional groups.

In this work, a photon- and metal-free approach for the radical fluorination of aliphatic oxalate-activated alcohols is reported.

Abstract

We present a photon- and metal-free approach for the radical fluorination of aliphatic oxalate-activated alcohols. The method relies on the spontaneous generation of the N-(chloromethyl)triethylenediamine radical dication, a potent single electron oxidant, from Selectfluor and 4-(dimethylamino)pyridine. The protocol is easily scalable and provides the desired fluorinated products within only a few minutes reaction time.

Metal-free deformylative/dehalogenative carbonylation, Michael addition of β-bromovinyl aldehydes for the synthesis of δ-oxo esters and vinyl ethers have been reported. Nucleophilic and organo-catalytic behaviour of DBU is explored and the regeneration of the parent starting material from the vinyl ether is also highlighted.

Abstract

Herein we have disclosed metal-free 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU)-catalyzed protocol for the deformylative/dehalogenative carbonylation and Michael addition of β-bromovinyl aldehydes with acrylates and carbonylation followed by etherification with benzyl bromides to synthesize δ-oxo esters and vinyl ethers respectively in good yields under an open atmosphere with broad substrate scope. Regeneration of starting material from vinyl ethers, organo-catalytic and nucleophilic behavior of DBU is also discussed.

A cross-electrophile coupling reaction of gem-difluoroalkenyl tosylate with α-CF₃ benzyl tosylate is presented. This protocol is the first example of cross-electrophile coupling between two different tosylates by Pd/Ni cooperative catalysis.

Abstract

Cross-electrophile coupling reactions are efficient for the construction of carbon-carbon bonds under relatively mild conditions, and hence widely used for making new molecules. Among various electrophiles, the cross-electrophile coupling reaction between two different tosylates has been rarely studied. Herein, we present a cross-electrophile coupling of gem-difluoroalkenyl tosylate (C(sp²)−OTs) and α-CF₃ benzyl tosylate (C(sp³)−OTs) by nickel/palladium cooperative catalysis. Mechanistic investigation indicated that the activation of C(sp²)−OTs bond and C(sp³)−OTs bond was facilitated by nickel and palladium respectively.

Asymmetric hydrofunctionalization of alkenes represents a powerful method to obtain valuable enantioenriched molecules from cheap and readily available materials. In this review, the recent advances in Palladium catalyzed asymmetric hydrofunctionalization of alkenes covering mainly contributions over the past decade are summarized. The remained challenges and opportunities in this field are also discussed.

Abstract

Palladium-catalyzed asymmetric hydrofunctionalization of alkenes is one of the most powerful and straightforward methods to forge a new C−H bond and a new C−X (X=C, N, O, F, Si etc) bond, which provides an efficient way to obtain valuable enantioenriched molecules from cheap and readily available feedstocks. Catalytic asymmetric hydrofunctionalization of simple alkenes is challenging but still highly sought after. This review will mainly focus on the recent advances in Palladium catalyzed asymmetric hydrofunctionalization of alkenes over the past decade, including hydroamination, hydrooxygenation, hydrofluorination, hydrosilylation, hydroarylation, hydroalkenylation and hydrocarbonylation.

The synthesis of densely functionalised spirocyclic products through a radical dearomative spirocyclisation chain mechanism is described. The spirocyclic products were converted into other spirocyclic scaffolds through a two-step ring expansion sequence.

Abstract

The dearomative spirocyclisation of benzisoxazoles through a radical chain mechanism is described. Densely functionalised spirocycles were prepared in high yields by reacting benzisoxazole-tethered ynones with aryl thiols in 1,2-dichloroethane (DCE) at 60 °C. The identification of stabilising three-electron interactions was key to the development of this new radical cascade reaction. The obtained spirocyclic products were converted into other spirocyclic scaffolds through a two-step hydrogenolysis-cyclisation sequence.

A metal-free defluoroborylation of 3,3-difluoropropenes has been developed. The reaction involves the convenient borylation agent B₂pin₂ and a combination of both TBAF and HMDS as an activating system. The fluorinated allylboronates were used as a platform to prepare functionalized monofluoroalkenes.

Abstract

The defluorinative functionalization of allylic fluorides represents an attractive approach for the preparation of molecules containing a monofluoroalkene core. In that sense, introducing a “boryl nucleophile” is a powerful strategy to obtain polyvalent borylated intermediates as versatile synthetic precursors. To perform this reaction without the use of transition metals, the nucleophilic character of a diborane/fluoride system was exploited in a S_N2′ type-substitution reaction of gem-difluoropropenes to install a pinacolborane group. The use of HMDS as a silylated additive is necessary to improve the reactivity. A direct oxidation of the intermediate boronates allowed the isolation of the corresponding β-fluoroallyl alcohols in low to good yields (9–81 %). Other synthetic transformations of a (2-fluoroallyl)boronate are also illustrated.

Inherent chirality represents a distinct form of molecular chirality that does not fit into the four traditional types of molecular chiral elements, which has been observed in a diverse range of molecular structures. This review summarizes the recent advances in the catalytic enantioselective synthesis of inherently chiral molecules, including chiral calixarenes, saddle-shaped chiral cycles, mechanically planar chiral rotaxanes and others.

Abstract

Inherent chirality represents a distinct category of molecular chirality that does not fall within the traditional classification of four chiral elements: central, axial, planar, and helical chirality. While extensive research has been conducted on the catalytic enantioselective construction of these conventional chiralities, the corresponding synthesis of inherently chiral molecules has remained largely unexplored. This minireview provides a comprehensive summary of recent advancements in this field, focusing on the catalytic asymmetric synthesis of inherently chiral calixarenes, saddle-shaped tetraphenylenes and their heterocycle derivatives, mechanically planar chiral rotaxanes and chiral multilayer 3D frameworks, as well as our perspective in this field.

This Review focuses on the very recent advances (from 2021 to the beginning of 2023) in the field of three-component reactions of quinoxalin-2(1H)-ones at the C3 position. According to the kind of radical types involved, some representative examples and detailed reaction mechanism have been categorized and discussed.

Abstract

The multicomponent reactions of quinoxalin-2(1H)-ones has attracted considerable interest due to their significant biological and chemical activities. The very recent advances (from 2021 to the beginning of 2023) on the radical three-component cascade reaction of quinoxalin-2(1H)-one derivatives at the C3 position were summarized in this mini-review. According to the kind of radical types involved, some representative examples and detailed reaction mechanism have been categorized and discussed.

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This Concept article summarises recent advances in approaches to the synthesis of important vinyl stannane building blocks in a stereocontrolled and regiocontrolled manner. Particular emphasis is put on those routes in which judicious choice of ligand affords a switchable reaction, providing routes to stereodefined olefins from a single starting material.

Abstract

Organostannanes have represented one of the most widely applied reagents in modern cross-coupling chemistry and represent a key reagent in the synthesis of a range of pharmaceutically relevant scaffolds. This Concept article reviews recent advances in approaches to the synthesis of these building blocks in a stereocontrolled and regiocontrolled manner. Particular focus is paid to methods which allow for divergent synthesis of alkenylstannanes and developments in methods which present opportunities for sustainable synthesis.