Tetrasubstituted Carbon Research Articles

Phosphine‐Catalyzed Domino Annulation Reactions of o‐Aminotrifluoroacetophenone Derivatives with Morita–Baylis–Hillman Carbonates: Construction of Tetrahydrofuro[3,2‐b]indolines

AbstractThe domino annulation reactions of o‐aminotrifluoroacetophenone derivatives and MBH carbonates enabled by PPh3 have been reported, which provide a series of tetrahydrofuro[3,2‐b]indolines containing a CF3‐substituted tetrasubstituted carbon stereocenters in yields of 74 to 95% and >20:1 dr. In this process, MBH carbonates were used as C1/C3 synthons. The MTT assay shows that the products exhibit the activity of inhibitory effect on proliferation on Hela cancer cell line.

Editing Tetrasubstituted Carbon: Dual C-O Bond Functionalization of Tertiary Alcohols Enabled by Palladium-Based Dyotropic Rearrangement.

Many elegant asymmetric syntheses of enantioenriched tertiary alcohols have been developed, and both the transition metal-catalyzed and the radical-based peripheral functionalization of tertiary alcohols have attracted intensive research interest in recent years. However, directly editing tetrasubstituted carbons remains challenging. Herein, we report a Pd-catalyzed migratory fluoroarylation reaction that converts tertiary alcohols to α-fluorinated tertiary alkyl ethers in good to excellent yields. An unprecedented 1,2-aryl/PdIV dyotropic rearrangement along the C-O bond, integrated in a PdII-catalyzed domino process, is key to the dual functionalization of both the hydroxyl group and the tetrasubstituted carbon. This reaction, which is compatible with a broad range of functional groups, generates a tertiary alkyl fluoride and an alkyl-aryl ether functional group with inversion of the absolute configuration at the tetrasubstituted stereocenter.

Carbon quaternization of redox active esters and olefins by decarboxylative coupling.

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (SH2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

Regioselective [3+2]‐Spiroannulation and [4+n]‐Annulation Approaches through Activation of C−H Bond Facilitated by Ru(II) as Catalyst: Role of Solvent Selectivity

AbstractRu(II)‐catalyzed and solvent‐switched [3+2]‐spiroannulation and [4+n] (n=1, 2, 3) annulations of 2‐aryl quinazolinone or 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with ynones or alkynyl alcohol or 1,3‐diynes under mild reaction conditions have been analyzed. These reactions take place in the presence of the appropriate solvent and features a redox‐neutral pathway. Ynone serves as an ‘atypical one‐carbon unit’ in [4+1] annulation and generates a tetrasubstituted carbon center bearing diverse heterocycles through [3+2] and [4+1] annulation strategies. Post transformations of the synthesized spiro‐products augments the potential of the developed methodology.

Catalytic Asymmetric Synthesis of α-Mono and α,α-Disubstituted 5- and 6-Membered α-Aza-lactams

AbstractFive- and six-membered cyclic amide structures with an embedded endocyclic α-aza group (α-aza-lactams) not only represent masked or protected forms of α-amino acids, but also form the core of other medicinally relevant compound families such as (thio)hydantoins and di(tri)ketopiperazines. In recent years, catalytic methods have been discovered to synthesize these molecular scaffolds, particularly those bearing an α-stereogenic tri- or tetrasubstituted carbon center, enantioselectively. The wide variety of methods and catalytic activation strategies that have been successfully applied to this end in a short period of years is notable. This short review covers the most significant, highlighting their differences and complementarities. The methods are organized according to the disconnection approach to the target α-aza-lactam structure, which in most cases is deeply bound to the type of catalysis applied.1 Introduction2 Catalyst-Controlled Cα–H Functionalization (Approach a)3 Decarboxylative α-AAA Reactions (Approach b)4 Cα–X Substitution Reactions (Approach c)5 De Novo Synthesis from Acyclic Precursors (Approach d)6 Hydrogenation of (Addition to) α-Alkyliden-α-aza-lactams (Approach e)7 Kinetic Resolution and Deracemization (Approach f)8 Conclusions

Construction of Diverse Pyrrolidine-Based Skeletons through the Ag-Catalyzed Stereoselective Addition-Elimination Reaction of Azomethine Ylides with Nitroallyl Acetates.

Because scaffold diversity has a pronounced impact on biological screening, the efficient and expedient construction of skeletally diverse compound collections is a fundamental demand in drug discovery. In this regard, we report here an asymmetric tandem conjugate addition-elimination reaction of pyrroline esters with nitroallyl acetates and its application to the construction of various types of fused or spirocyclic pyrrolidines. A AgOAc/(R,Sp)-ThioClickFerrophos (TCF) catalyst efficiently promotes the addition-elimination reaction, setting vicinal chiral stereocenters featuring a tetrasubstituted carbon with excellent enantio- and diastereoselectivity while leaving the versatile nitroolefin moiety. The broad substrate scope of this reaction and the transformability of the resulting nitroolefin, imine, and ester moieties allow for the construction of diverse pyrrolidine-based fused or spiro bicyclic skeletons in optically active forms by various intramolecular cyclization processes.

Construction of halogenated tetrasubstituted carbon centers through copper(I)-catalyzed asymmetric alkylation of 2-azaarylesters

Construction of halogenated tetrasubstituted carbon centers through copper(I)-catalyzed asymmetric alkylation of 2-azaarylesters

Why pyrrolidines did not work in the alkylation–cyclization–isomerization–3-aza-Cope cascade?

Alkylation–cyclization–isomerization–3-aza-Cope cascade is a powerful method for constructing fused nitrogen heterocycles bearing tetrasubstituted carbons. Despite this, the use of pyrrolidines as starting substrates in these reactions remains limited. In our study, we conducted a detailed analysis of the cascade product using OTBS-substituted pyrrolidine. Our findings revealed that the main product was a nine-five-membered bicyclic enamine, which formed through a 3-aza-Cope rearrangement from syn-vinylammonium. Further, our comprehensive DFT calculations of the transition states of the 3-aza-Cope rearrangement from both anti- and syn-dienolates and vinylammoniums demonstrated that the rearrangement from syn-vinylammonium was more favorable. This preference stems from its progression through a late transition state that minimizes distortion of the pyrrolidine ring. These findings enhance our understanding of the mechanism and facilitate the prediction of outcomes of future cascade reactions.

B(C6F5)3-catalyzed regio- and stereoselective cyanation of isatogens and their derivatives

Herein we report the regioselective cyanation of isatogen (3-indolone N-oxide) and its derivatives. The high electrophilicity of isatogen is a key feature for their various chemical transformations, and we describe a new application to use boron catalyst for regio- and stereoselective cyanation at C2 position of isatogen. The combination of B(C6F5)3 and Me3SiCN is optimal, and the C2-cyano adducts are exclusively obtained in up to quantitative yield. In addition, isatogenol that includes a tertiary hydroxyl group at C3 position is also suitable for this cyanation to create consecutive tetra-substituted carbons with high stereoselectivity.

Organocatalyzed diastereoselective cyclization of β-alkyl nitroolefins with alkylidene malononitriles: new approach to azetidine nitrones and isoxazoles

An organocatalytic domino reaction of β-alkyl nitroolefins with alkylidene malononitriles to give azetidine nitrones with good diastereoselectivities is reported. The in situ-generated nitrones were transmuted into isoxazoles catalyzed by acid.

Modular dehydrogenative cross-nucleophile coupling for direct construction of tetrasubstituted carbons

An FeCl3-catalyzed cross-dehydrogenative coupling reaction for the construction of various types of C–Y (Y = C, N, O, S) bonds with air as a green oxidant.

Asymmetric Paired Electrocatalysis: Enantioselective Olefin-Sulfonylimine Coupling.

Asymmetric electrocatalysis offers exciting new strategies for the synthesis of chiral molecules through novel reaction pathways. However, simultaneous activation of reactants on both electrodes via asymmetric paired electrolysis, which is more energy efficient and economic than single half-electrode synthesis, remains a formidable challenge. Herein, an asymmetric olefin-sulfonylimine coupling via paired electrocatalysis is presented for the first time. In this protocol, Co-catalyzed hydrogen atom transfer on the anode and Ni-catalyzed sulfonylimine reduction on the cathode were seamlessly cross-coupled. The new catalytic system enables the formation of chiral amine products bearing a tetrasubstituted carbon stereocenter with a high enantioselectivity (up to 96% ee).

Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction.

Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group.

Aza‐Prins Cyclization on Ketones to Access Piperidines with Tetrasubstituted Carbon Stereocenters

AbstractThe aza‐Prins cyclization in presence of a variety of aliphatic, aromatic, and heterocyclic ketones is disclosed. The developed method allows an access to diverse C‐2 functionalized piperidines, bearing a tetrasubstituted or spiranic carbon stereocenter, in a range of 30 to 87% yields. When diastereomers were formed, the trans isomer was identified as the major product.

Access to Multifunctionalized Tetrasubstituted Carbon Centers Bearing up to Three Different Heteroatoms via Tandem Geminal Chlorofluorination of 1,2-Dicarbonyl Compounds.

The incorporation of noncarbon heteroatoms into organic molecules typically instills characteristic and often valuable functionalities. The copresence of different heteroatoms can further broaden their utility through the synergistic cooperative effects, which may even lead to the discovery of formerly unavailable properties that are not just a simple accumulation of each function. However, despite increasing interest in the controllable installation of heteroatoms, it has been extremely challenging to construct carbon centers having three different heteroatoms in a synthetically useful manner. In this work, our group's tandem geminal chlorofluorination (Cl, F) strategy was applied to rationally designed heteroatom-bearing 1,2-dicarbonyl substrates, including α-keto thioesters (S), α-keto N-acylindoles (N), and α-keto acylsilane (Si), which resulted in the practical production of doubly or triply heterofunctionalized tetrasubstituted carbon centers with excellent site-selectivity.

Direct Regioselective Reductive Allylation of Imines: Application to Synthesis of Oxazines with Halogenated Reagent.

Oxazines are an important class of compounds in oxazine ligands and medical chemistry. Here, we describe a linear-selective allylation of imines with allyl electrophiles via cross-electrophile coupling reactions, followed by cyclization with halogenated reagents, providing a new strategy to afford oxazine compounds with a tetrasubstituted carbon center. Mechanistic studies indicate that α-amino carbanion, generated by successive single-electron transfer processes, is a key intermediate for nucleophile attack on π-allylpalladium in photoredox/palladium catalysis.

Enantio- and Diastereoselective Copper-Catalyzed Synthesis of Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters.

A Cu-catalyzed coupling of cyclic imino esters with 2H-azirines has been developed to synthesize novel optically active aziridines in high yields with excellent levels of diastereo- and enantioselectivities under mild conditions. This novel protocol features a broad substrate scope and good functional group compatibility, and it enriches the existing reaction type of rapid synthesis of optically active aziridines bearing vicinal tetrasubstituted stereogenic carbon centers.

Photocatalytic Dearomative Intermolecular Seven‐Membered Ring Construction of Benzofurans

AbstractWe report the synthesis of seven‐membered carbocycles through the dearomative intermolecular reaction of benzofurans with vinylcyclopropanes. The significant feature of this method involves activating benzofurans through energy transfer from an activated photocatalyst. Substituent effects were investigated for each substrate, and hydrocyclohepta[b]benzofurans with a tetrasubstituted carbon were obtained as a single diastereomer. This synthetic approach compliments the reported methodologies for synthesizing this type of skeleton and introduces a new feedstock for this skeleton with a different substitution pattern. Computational studies of the reaction mechanism suggested that the reaction proceeds stepwise through addition, small ring opening, and re‐cyclization. This novel synthetic approach opens up new possibilities for efficiently constructing seven‐membered carbocycles. Moreover, it provides a valuable platform for discovering unique molecules with diverse substitution patterns.

Regioselective Construction of Indolylated Cyclic Tetrasubstituted Carbon Centers through Brønsted Acid‐Catalyzed Dearomative Skeletal Rearrangement of Azofurans

AbstractA Brønsted acid‐catalyzed dearomative skeletal rearrangement of azofurans with indoles is reported, enabling a regioselective 1,6‐addition, ring‐opening and 1,4‐addition cascade to produce 26 examples of indolylated pyrrol‐2‐ones with a cyclic tetrasubstituted stereocenter in 58–94% yields. This protocol demonstrates remarkable compatibility regarding azofurans and indoles with different substitution patterns, featuring complete regioselectivity.

Palladium-Catalyzed Intermolecular Dearomatization Annulation Cascade Reaction of Furans for Stereoselective Access to 2,5-Dihydrofurans.

A novel palladium-catalyzed intermolecular dearomatization of furans with alkynes via a three-component formal [3 + 2] spiroannulation/allylic substitution cascade reaction has been successfully developed for the stereoselective assembly of spiro 2,5-dihydrofuran frameworks. High step economy and efficacy as well as excellent stereoselectivity were achieved for a broad substrate scope. Two new C-C bonds and one new C-O bond were generated sequentially in a one-pot manipulation. The yielded spiro 2,5-dihydrofuran skeleton bearing a tetrasubstituted carbon center constitutes the core structure for plenty of useful natural products or corresponding analogues. This work represents a significant advancement in the dearomatization strategy for furan heterocycles and provides a practical methodology for expedited access to complex spiro dihydrofuran scaffolds.