Transition Metal Catalyzed Free-Amine (-NH2 ) Directed C-H Bond Activation and Functionalization for Biaryl Frameworks.

Transition-metal-catalyzed direct transformation of inert C-H bond has revolutionized the arsenal of main-stream organic synthesis, providing a new upfront to forge structurally enriched and biologically relevant scaffolds in a step- and atom-economical way. Past decades have accounted for the major developments in this realm, proclaiming excellent site-selectivity by exploiting a variety of coordinating directing groups (DGs). Consideration of versatile, abundant, sp3 -hybridized free-amine (-NH2 ) functionality for the same purpose has always been a formidable task owing to its innate reactivity. In recent years, free-amine functionality has emerged as a potent DG for a wide range of C-C and C-heteroatom bonds formations and annulation cascades. In this review article, we have discussed the advancements of free-amine directed C-H activation/functionalization reactions towards biaryl frameworks made within a decade (2012 to 2021).

Regioselective C-H Alkenylation and Unsymmetrical Bis-olefination of Heteroarene Carboxylic Acids with Ruthenium Catalysis in Water.

An efficient weak carboxylate-assisted oxidative cross-dehydrogenative C-H/C-H coupling (CDC) of heteroarenes with readily available olefins has been devised employing water as green solvent under ruthenium(II) catalysis. The reaction is operationally simple, accommodates a large variety of heteroaromatic carboxylic acids as well as olefins, and facilitates a diverse array of high-value olefin-tethered heteroarenes in high yields (up to 87%). The potential of this ortho-C-H bond activation strategy has also been exploited toward tunable synthesis of densely functionalized heteroarenes through challenging unsymmetrical bis-olefination process in a one-pot sequential fashion. Mechanistic investigation demonstrates a reversible ruthenation process and C-H metalation step might not be involved in the rate-determining step.

Efficient and recyclable palladium enriched magnetic nanocatalyst for reduction of toxic environmental pollutants.

In this paper, highly stable, powerful, and recyclable magnetic nanoparticles tethered N-heterocyclic carbene-palladium(II) ((CH3)3-NHC-Pd@Fe3O4) as magnetic nanocatalyst was successfully synthesized from a simplistic multistep synthesis under aerobic conditions through easily available low-cost chemicals. Newly synthesized (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst was characterized from various analytical tools and catalytic potential of the (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst was studied for the catalytic reduction of toxic 4-nitrophenol (4-NP), hexavalent chromium (Cr(VI)), Methylene Blue (MB) and Methyl Orange (MO) at room temperature in aqueous media. UV-Visible spectroscopy was employed to monitor the reduction reactions. New (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst exhibited excellent catalytic activity for the reduction of toxic environmental pollutants. Moreover, (CH3)3-NHC-Pd@Fe3O4 magnetic nanocatalyst could be easily and rapidly separated from the reaction mixture with the help of an external magnet and recycled minimum five times in reduction of 4-NP, MB, MO and four times in Cr(VI) without significant loss of catalytic potential and remains stable even after reuse.

Nickel-Catalyzed Direct Alkenylation of Methyl Heteroarenes with Primary Alcohols.

An efficient nickel-catalyzed acceptorless dehydrogenative coupling of methyl-substituted heteroarenes with primary alcohols is achieved using an in situ generated complex of inexpensive NiBr2 and readily available 8-aminoquinoline picolinic amide ligand. The protocol is operationally simple and scalable and furnishes a series of high-value 2-alkenylheteroarenes in good yields (up to 88%) with exclusive E-selectivity. The reaction proceeds with the release of water and molecular hydrogen, which was analyzed through gas chromatography to validate the reaction mechanism.

Oxidative cross-dehydrogenative [2 + 3] annulation of α-amino ketones with α-keto esters: concise synthesis of clausenamide analogues.

A one-pot oxidative cross-dehydrogenative [2 + 3] annulation of α-amino ketones with α-keto esters at room temperature is reported. The protocol features copper/organo cooperative catalysis and provides densely functionalized pyrrolones in high yields. Subsequent reduction furnished multi-substituted pyrrolidinones which represent the core-structure of the natural product clausenamide, a lead molecule for the treatment of Alzheimer's disease.

Metal-free switchable ortho/ipso-cyclization of N-aryl alkynamides: divergent synthesis of 3-selenyl quinolin-2-ones and azaspiro[4,5]trienones.

A selenium radical triggered switchable ortho/ipso-cyclization cascade of N-aryl alkynamides has been devised under metal-free conditions to access 3-selenyl quinolin-2-ones and 3-selenospiro[4,5]trienones in high yields (up to 98%). The simple protocol is scalable and the mechanistic studies suggest that the radical cascade proceeds through a spirocyclic intermediate which is formed via an intramolecular ipso-cyclization route.

A Cross-Dehydrogenative Annulation Strategy towards Synthesis of Polyfluorinated Phenanthridinones with Copper.

The first cross-dehydrogenative annulation of (hetero)aromatic amides with polyfluoro(hetero)arenes is presented. This operationally simple oxidative annulation process is mediated by inexpensive copper salt, accommodates a wide range of substrates with exquisite chemo- and regioselectivity profile, and produces demanding polyfluorinated phenanthridinones in high yields (up to 92 %). Using alkenyl amides under identical conditions, the synthesis of polyfluorinated 2-quinolones has also been accomplished. Given the importance of fluorinated heterocycles in the pharmaceutical industry and drug discovery, this work is highly significant.

Directed C-H Bond Functionalization: A Unified Approach to Formal Syntheses of Amorfrutin A, Cajaninstilbene Acid, Hydrangenol, and Macrophyllol.

Formal syntheses of natural products amorfrutin A, cajaninstilbene acid, hydrangenol, and macrophyllol have been accomplished on the basis of successive C-H bond functionalization of ready-stock benzoic acids. This concise strategy involves transition-metal-catalyzed directed C-H olefination, C-H hydroxylation, and acid-mediated C-H prenylation as key steps.

Copper Catalyzed C-N Cross-Coupling Reaction of Aryl Boronic Acids at Room Temperature through Chelation Assistance.

A copper-catalyzed selective C-N cross-coupling has been developed based on chelation-assisted amidation of readily available aryl boronic acids at room-temperature under open-flask conditions. The reaction is scalable and tolerates a wide spectrum of functional groups delivering fully substituted unsymmetrical amides in high yields (up to 96%). The C-N cross coupling also established with aryl silanes, extending the palette of coupling partners of this strategy.

Copper-Catalyzed 8-Amido Chelation-Induced Remote C-H Amination of Quinolines.

A copper-catalyzed 8-amide chelation-induced remote C-H amination of quinolines has been developed. This direct amination with readily available azodicarboxylates proceeded with perfect C5-regioselectivity offering amino-substituted 8-aminoquinolines, important bioactive molecular scaffolds, in very high yields (up to 96%). A single-electron transfer (SET)-mediated mechanism with kH /kD =1.1 was proposed after trapping of the radical intermediate.

Correction: Pyrido[1,2-a]pyrimidinium ions - a novel bridgehead nitrogen heterocycles: synthesis, characterisation, and elucidation of DNA binding and cell imaging properties.

Correction for 'Pyrido[1,2-a]pyrimidinium ions - a novel bridgehead nitrogen heterocycles: synthesis, characterisation, and elucidation of DNA binding and cell imaging properties' by Susanta Kumar Manna et al., Org. Biomol. Chem., 2015, 13, 8037-8047.

Scales of Lewis basicities toward C-centered Lewis acids (carbocations).

Equilibria for the reactions of benzhydryl cations (Ar2CH(+)) with phosphines, tert-amines, pyridines, and related Lewis bases were determined photometrically in CH2Cl2 and CH3CN solution at 20 °C. The measured equilibrium constants can be expressed by the sum of two parameters, defined as the Lewis Acidity (LA) of the benzhydrylium ions and the Lewis basicity (LB) of the phosphines, pyridines, etc. Least-squares minimization of log K = LA + LB with the definition LA = 0 for (4-MeOC6H4)2CH(+) gave a Lewis acidity scale for 18 benzhydrylium ions covering 18 orders of magnitude in CH2Cl2 as well as Lewis basicities (with respect to C-centered Lewis acids) for 56 bases. The Lewis acidities correlated linearly with the quantum chemically calculated (B3LYP/6-311++G(3df,2pd)//B3LYP/6-31G(d,p) level) methyl anion affinities of the corresponding benzhydrylium ions, which can be used as reference compounds for characterizing a wide variety of Lewis bases. The equilibrium measurements were complemented by isothermal titration calorimetry studies. Rates of SN1 solvolyses of benzhydryl chlorides, bromides, and tosylates derived from E(13-33)(+), i.e., from highly reactive carbocations, correlate excellently with the corresponding Lewis acidities and the quantum chemically calculated methyl anion affinities. This correlation does not hold for solvolyses of derivatives of the better stabilized amino-substituted benzhydrylium ions E(1-12)(+). In contrast, the correlation between electrophilic reactivities and Lewis acidities (or methyl anion affinities) is linear for all donor-substituted benzhydrylium ions E(1-21)(+), while the acceptor-substituted benzhydrylium ions E(26-33)(+) react more slowly than expected from their thermodynamic stabilities. The boundaries of linear rate-equilibrium relationships were thus defined.

Pyrido[1,2-a]pyrimidinium ions--a novel bridgehead nitrogen heterocycles: synthesis, characterisation, and elucidation of DNA binding and cell imaging properties.

A novel class of bridgehead nitrogen heterocycles, pyrido[1,2-a]pyrimidinium ions, has been readily synthesized by a two-step one-pot reaction in high yields (up to 93%). These ionic compounds are bench stable and moisture tolerant and have highly fluorescent properties (quantum yield up to 0.65). A characteristic bright bluish fluorescence was observed in polar solvents such as acetonitrile and fluorescent intensity gradually diminishes with decreasing the polarity of the medium, which becomes almost negligible in toluene. These compounds also show interesting bioactivity. DNA interaction, imaging, and viability experiments with human leukemic Jurkat and KG-1A cells revealed that they are potential candidates for cancer diagnosis.

Free Amine-Directed Redox Neutral Ruthenium(II) Catalysis toward Regioselective Synthesis of Heterobiaryls.

A regioselective coupling of ortho-heteroaryl anilines and 7-oxabenzonorbornadienes has been developed by leveraging free amine-directed redox-neutral Ru(II) catalysis. This protocol facilitates formal C-2 arylation of the indole moiety under mild conditions to offer valuable heterobiaryls in high yields. The reaction displays a broad substrate generality and scalability and retains efficacy in the presence of diverse pharmacophore scaffolds. Moreover, products bearing a free amine group were successfully employed in Mg(NTf2)2-catalyzed double Michael addition cascade, which led to the synthesis of intricate indole- and pyrrole-fused azaheterocycles.

Three-component dicarbofunctionalization of allylamines via nucleopalladation pathway: unlocking vicinal and geminal selectivity.

A palladium(ii)-catalyzed vicinal as well as geminal selective dicarbofunctionalization of allylamine embedded in a removable picolinamide auxiliary is developed by exploiting a nucleopalladation-triggered intermolecular three-component coupling reaction. The vicinal selectivity was accomplished by engaging allylamine, indoles, and aryl or styrenyl halides through a Pd(ii)/Pd(iv) reaction manifold, while the two-fold coupling of allylamine and indoles via a Pd(ii)/Pd(0) reaction modality resulted in geminal selectivity. The protocol is operationally simple, scalable, and offers two distinct types of products bearing functionalized tryptamine and bisindolyl frameworks in very high to excellent yields. The reaction features a wide substrate generality and also remains effective in the presence of various medicinally relevant scaffolds. Notably, this work represents the first example of nucleopalladation-guided intermolecular dicarbofunctionalization of allylamines.

A Visible-Light-Induced α-Aminoalkyl-Radical-Mediated Halogen-Atom Transfer Process: Modular Synthesis of Phenanthridinone Alkaloids.

A halogen-atom transfer (XAT) strategy utilizing α-aminoalkyl radicals allows the generation of aryl radicals at room temperature, which is applied for intramolecular cyclization reactions en route to biologically relevant alkaloids. Starting from simple halogen-substituted benzamides under visible light irradiation in the presence of an organophotocatalyst (4CzIPN) and nBu3N allows the modular construction of the phenanthridinone core, which gives facile access to drug analogs and alkaloids, e.g., from the Amaryllidaceae family. The reaction pathway most likely involves a quantum mechanical tunneling enabled transfer event to achieve aromatization-halogen-atom transfer.

Ru(II)-Catalyzed Oxidative Cross-Dehydrogenative Alkenylations of Aromatic Amides and Ketones with Unactivated Olefins.

A weak coordination guided Ru(II)-catalyzed oxidative functionalization of arenes with unactivated olefins is developed, offering a wide variety of ortho-alkenylated benzamides, acetophenones, and benzophenone in high yields. The protocol accommodates several bioactive molecules and allows downstream synthetic manipulations leading to a 2,3-benzodiazepine scaffold. The reaction features a reversible metalation step and favors a regioselective ß-hydride elimination event.

Brønsted acid-catalyzed annulation reaction of hydroxamic acids: synthesis of cyclopentane-fused isoxazolidines and their benzilic amide rearrangement.

Readily available hydroxamic acids were leveraged to access challenging nitrones in the presence of H3PO4 as a Brønsted acid catalyst and engaged in an intramolecular (3+2) annulation reaction to make valuable cyclopentane-fused isoxazolidines with high yields and excellent diastereoselectivity. The products were further utilized in a unique base-promoted benzilic amide rearrangement to provide cyclopentane-fused γ-lactams bearing three contiguous stereocenters as a single diastereomer.

Enaminone-directed ruthenium(II)-catalyzed C-H activation and annulation of arenes with diazonaphthoquinones for polycyclic benzocoumarins.

The weakly coordinating enaminone functionality has been leveraged for a C-H bond activation strategy under ruthenium catalysis and employed in the regioselective annulative coupling of arenes with diazonaphthoquinones, offering polycyclic benzocoumarins in very high yields. The enaminone motif plays a dual role and the protocol operates through a Ru(II)/Ru(IV) catalytic pathway which is amenable to the diversification of various pharmacophore-coupled substrates.

Regio- and Stereoselective Allylation of Anilines with Aryl Allenes in Hexafluoroisopropanol Solvent.

A regio- and stereoselective allylation of N-unsubstituted anilines has been developed that explores aryl allenes as masked allyl synthons and a combination of Mg(OTf)2/HFIP as an effective proton source. The protocol is operationally simple and scalable and offers high yields of diverse p-allyl anilines bearing an olefin motif with exclusive E-geometry. The methodology was also suitable for the regioselective allylation of indole and can be advanced in a three-component reaction mode using NIS activator. The alteration of the catalytic system with TfOH resulted in the regioselective difunctionalization of allenes, which follows an allylation/hydroarylation cascade.