Substrate-controlled divergent remote C-H and N-H polyfluoroarylation of 2-aminopyrimidines with polyfluoroarenes via Pd(II)/Pd(0) catalysis.

Substrate-controlled product divergence in the reaction of 2-aminopyrimidines with polyfluoroarenes under palladium catalysis is demonstrated for the first time. The reaction of secondary N-alkylpyrimidine-2-amines with polyfluoroarenes leads to C5-H polyfluoroarylation via C-H/C-H coupling, while secondary N-aryl substituents yield N-H polyfluoroarylation, forming triarylamines.

Divergent Synthesis of Pyrazoles via Manganese Pincer Complex Catalyzed Acceptorless Dehydrogenative Coupling Reactions.

This report detailed the synthesis of multi-substituted pyrazoles through the acceptorless dehydrogenative coupling (ADC) reaction catalyzed by a well-defined manganese(I)-pincer complex. Symmetrically substituted pyrazoles were synthesized by reacting 1,3-diols with hydrazines. Unsymmetrically substituted pyrazoles were selectively made via the ADC of primary alcohols with methyl hydrazones. Water and hydrogen are liberated as the green byproducts. The endurance of these methodologies has been presented by producing 30 substrates with varied functionalities. Model reactions were scaled up to demonstrate practicability. The reaction rate and order were measured to transparent the involvement of the reagents during catalysis. Control experiments elucidated the plausible reaction mechanisms.

Catalytic acceptorless dehydrogenative borylation of styrenes enabled by a molecularly defined manganese complex.

In this study, we employed a 3d metal complex as a catalyst to synthesize alkenyl boronate esters through the dehydrogenative coupling of styrenes and pinacolborane. The process generates hydrogen gas as the sole byproduct without requiring an acceptor, rendering it environmentally friendly and atom-efficient. This methodology demonstrated exceptional selectivity for dehydrogenative borylation over direct hydroboration. Additionally, it exhibited a preference for borylating aromatic alkenes over aliphatic ones. Notably, derivatives of natural products and bioactive molecules successfully underwent diversification using this approach. The alkenyl boronate esters served as precursors for the synthesis of various pharmaceuticals and potential anticancer agents. Our research involved comprehensive experimental and computational studies to elucidate the reaction pathway, highlighting the B-H bond cleavage as the rate-determining step. The catalyst's success was attributed to the hemilability and metal-ligand bifunctionality of the ligand backbone.

Rejuvenation of dearomative cycloaddition reactions via visible light energy transfer catalysis.

Dearomative cycloaddition is a powerful technique to access sp3-rich three-dimensional structural motifs from simple flat, aromatic feedstock. The building-up of unprecedentedly diverse polycyclic scaffolds with increased saturation and stereochemical information having various applications ranging from pharmaceutical to material sciences, is an essential goal in organic chemistry. However, the requirement of large energy inputs to disrupt the aromaticity of an arene moiety necessitates harsh reaction conditions for ground state dearomative cycloaddition. The photochemical requirement encompasses use of ultraviolet (UV) light to enable the reaction on an excited potential energy surface. The microscopic reversibility under thermal conditions and the use of high energy harmful UV irradiation in photochemical manoeuvres, however, constrain their widespread use from a synthetic point of view. In this context, the recent renaissance of visible light energy transfer (EnT) catalysis has become a powerful tool to initiate dearomative cycloaddition as a greener and more sustainable approach. The excited triplet state population is achieved by triplet energy transfer from the appropriate photosensitizer to the substrate. While employing mild visible light energy as fuel, the process leverages an enormous potential of excited state reactivity. The discovery of an impressive portfolio of organic and inorganic photosensitizers with a range of triplet energies facilitates visible light photosensitized dearomative cycloaddition of various substrates to form sp3-rich fused polycyclic architectures with diverse applications. The tutorial review comprehensively surveys the reawakening of dearomative cycloadditions via visible light-mediated energy transfer catalysis in the past five years. The progress ranges from intra- and intermolecular [2π + 2π] to [4π + 2π], and ends at intermolecular [2π + 2σ] cycloadditions. Furthermore, the review provides potential possibilities for future growth in the growing field of visible light energy transfer catalysis.

DFT-Guided Mechanistic Insights into Chemodivergence: A Mixed Explicit-Implicit Solvent Description to Dictate the Chemoselectivity.

Herein we report a density functional theory (DFT)-guided mechanistic investigation of the nitrile reduction reaction, which exhibits a solvent-dependent chemodivergence. This study reveals an interesting mechanistic picture, highlighting the exact role of a protic solvent, isopropanol, in regulating the reaction outcome. The explicit solvent effect involving polar protic isopropanol favors imine metathesis by proton hopping through stepwise addition and elimination steps and thus produces a secondary amine as the final product. In contrast, the nonpolar solvent n-hexane is incapable of facilitating the proton migration and stops the solvent-assisted imine metathesis. As a result, only primary amines are obtained as the final product. This DFT study provides a recipe for the choice of solvents that can dictate chemoselectivity in product formation.

A π-conjugated covalent organic framework enables interlocked nickel/photoredox catalysis for light-harvesting cross-coupling reactions.

Covalent organic frameworks (COFs) are an outstanding platform for heterogeneous photocatalysis. Herein, we synthesized a pyrene-based two-dimensional C[double bond, length as m-dash]C linked π-conjugated COF via Knoevenagel condensation and anchored Ni(ii)-centers through bipyridine moieties. Instead of traditional dual metallaphotoredox catalysis, the mono-metal decorated Ni@Bpy-sp2c-COF interlocked the catalysis mediated by light and the transition metal. Under light irradiation, enhanced energy and electron transfer in the COF backbone, as delineated by the photoluminescence, electrochemical, and control experiments, expedited the excitation of Ni centers to efficiently catalyze diverse photocatalytic C-X (X = B, C, N, O, P, S) cross-coupling reactions with efficiencies orders of magnitude higher than the homogeneous controls. The COF catalyst tolerated a diverse range of coupling partners with various steric and electronic properties, delivering the products with up to 99% yields. Some reactions were performed on a gram scale and were applied to diversify pharmaceuticals and complex molecules to demonstrate the synthetic utility.

Asymmetric alkene-alkene reductive cross-coupling reaction via visible-light photoredox/cobalt dual catalysis.

The first example of asymmetric alkene-alkene reductive coupling is demonstrated via visible-light-fueled photoredox/cobalt dual catalysis. The desymmetrization reaction provided products (>20 examples) with up to five chiral centers in single-step operation in up to 95% yields with very high relative (>99 : 1 dr) and absolute stereochemistry (up to 98 : 2 er) control. The preliminary mechanistic investigations suggested that the critical mechanistic steps involved light-mediated controlled low-valent cobalt complex generation, oxidative ene-ene cyclization, and protonation.

Direct C(3)5-H Polyfluoroarylation of 2-Amino/alkoxy Pyridines Enabled by a Transient and Electron-deficient Palladium Intermediate.

Herein, we present an unprecedented azine-limited C5-H polyfluoroarylation of 2-aminopyridines enabled by a transient and electron-deficient perfluoroaryl-Pd species via C-H/C-H coupling. The protocol further allows C3(5)-H polyfluoroarylation of 2-alkoxypyridines guided by sterics and electronics for the first time. The late-stage C-H functionalization of drugs, drug derivatives, and natural product derivatives and synthesis of C5-aryl drug derivatives further demonstrated the method's utility. The preliminary mechanistic studies reveal that the synergistic combination of the bulky yet electrophilic perfluoroaryl-Pd species and the partial nucleophilicity of the C5-position of 2-amino/alkoxy-pyridines is the origin of reactivity and selectivity. Importantly, the first experimental evidence for the role of diisopropyl sulfide is provided.

Visiblelight-induced ternary electron donor-acceptor complex enabled synthesis of 2-(2-hydrazinyl) thiazole derivatives and the assessment of their antioxidant and antidiabetic therapeutic potential.

A mild and eco-friendly visible-light-induced synthesis of 2-(2-hydrazinyl) thiazole from readily accessible thiosemicarbazide, carbonyl, and phenacyl bromide in the absence of a metal catalyst and/or any extrinsic photosensitizer is reported. This approach only requires a source of visible light and a green solvent at room temperature to produce the medicinally privileged scaffolds of hydrazinyl-thiazole derivatives in good to outstanding yields. Experimental studies support the in situ formation of a visible-light-absorbing, photosensitized colored ternary EDA complex. The next step is to prepare a pair of radicals in an excited state, which makes it easier to prepare thiazole derivatives through a SET and PCET process. DFT calculations additionally supported the mechanistic analysis of the course of the reaction. The antioxidant and antidiabetic properties of some of the compounds in the synthesized library were tested in vitro. All the investigated compounds demonstrated appreciable antioxidant activity, as evidenced by the reducing power experiment and the IC50 values of the DPPH radical scavenging experiment. Furthermore, the IC50 values for 4c, 4d, and 4g also demonstrated a strong α-amylase inhibitory effect.

Sustainable Synthesis of α-Hydroxycarboxylic Acids by Manganese Catalyzed Acceptorless Dehydrogenative Coupling of Ethylene Glycol and Primary Alcohols.

Herein, we report a straightforward synthesis of valuable α-hydroxycarboxylic acid molecules via an acceptorless dehydrogenative coupling of ethylene glycol and primary alcohols. A bench-stable manganese complex catalyzed the reaction, which is scalable, with the product being isolated with high yields and selectivities under mild conditions. The protocol is environmentally benign, producing water and hydrogen gas as the only byproducts. Methanol can also be used as a C1 source for producing the platform molecule lactic acid, with a high turnover of >104 . The methodology was also used to functionalize alcohols derived from natural products and fatty acids. Furthermore, it was applied for synthesizing α-amino acid, α-thiocarboxylic acid, and several drugs and bioactive molecules, including endogenous metabolites, Danshensu, Enalapril, Lisinopril, and Rosmarinic acid. Preliminary mechanistic studies were performed to shed light on the mechanism involved in the reaction.

Ruthenium-Catalyzed Reductive Coupling of Epoxides with Primary Alcohols via Hydrogen Transfer Catalysis.

Herein, we report the ruthenium-catalyzed synthesis of ß-alkylated secondary alcohols via the regioselective ring-opening of epoxides with feedstock primary alcohols. The reaction utilized alcohol as the carbon source and the terminal reductant. Kinetic and labeling experiments elucidate the hydrogen transfer catalysis that operates via tandem Markovnikov selective transfer hydrogenation of terminal epoxides and hydrogen transfer-mediated cross-coupling of the resulting alcohol with primary alcohol substrates. A broad scope (40 examples including drugs/natural product derivatives) and excellent regioselectivity for a variety of substrates were shown.

Intermolecular dearomative [4 + 2] cycloaddition of naphthalenes via visible-light energy-transfer-catalysis.

The dearomative cycloaddition reaction serves as a blueprint for creating sp3-rich three-dimensional molecular topology from flat-aromatic compounds. However, severe reactivity and selectivity issues make this process arduous. Herein, we describe visible-light energy-transfer catalysis for the intermolecular dearomative [4 + 2] cycloaddition reaction of feedstock naphthalene molecules with vinyl benzenes. Tolerating a wide range of functional groups, structurally diverse 2-acyl naphthalenes and styrenes could easily be converted to a diverse range of bicyclo[2.2.2]octa-2,5-diene scaffolds in high yields and moderate endo-selectivities. The late-stage modification of the derivatives of pharmaceutical agents further demonstrated the broad potentiality of this methodology. The efficacy of the introduced methods was further highlighted by the post-synthetic diversification of the products. Furthermore, photoluminescence, electrochemical, kinetic, control experiments, and density-functional theory calculations support energy-transfer catalysis.

Enantioselective C-H bond functionalization of aromatic ketones with 1,6-enynes via photoredox/cobalt dual catalysis.

An enantioselective ortho-C(sp2)-H functionalization of ketones with 1,6-enynes is demonstrated via photoredox/cobalt dual catalysis. The method exhibits high yields, functional group tolerance, and selectivity. Mechanistic studies suggested the operation of visible-light mediated low-valent cobalt complex generation, intramolecular cyclization, ortho-C-H bond insertion, and reductive elimination as the key mechanistic steps.

Dicarbofunctionalizations of an Unactivated Alkene via Photoredox/Nickel Dual Catalysis.

1,2-Dicarbofunctionalization of unactivated olefin has been reported under photoredox/nickel dual catalysis. The mildness of the visible-light-mediated reaction allows the use of various alkyl and aryl electrophiles with several sensitive functional groups. The protocol was equally applied for late-stage diversification of drugs and biologically active molecules. Investigations elucidated the importance of photoredox/nickel dual catalysis and α-amino-radical-mediated halogen atom transfer and provided us with the nickel complexes involved in the reaction.

Manganese-catalyzed hydrogenation, dehydrogenation, and hydroelementation reactions.

The emerging field of organometallic catalysis has shifted towards research on Earth-abundant transition metals due to their ready availability, economic advantage, and novel properties. In this case, manganese, the third most abundant transition-metal in the Earth's crust, has emerged as one of the leading competitors. Accordingly, a large number of molecularly-defined Mn-complexes has been synthesized and employed for hydrogenation, dehydrogenation, and hydroelementation reactions. In this regard, catalyst design is based on three pillars, namely, metal-ligand bifunctionality, ligand hemilability, and redox activity. Indeed, the developed catalysts not only differ in the number of chelating atoms they possess but also their working principles, thereby leading to different turnover numbers for product molecules. Hence, the critical assessment of molecularly defined manganese catalysts in terms of chelating atoms, reaction conditions, mechanistic pathway, and product turnover number is significant. Herein, we analyze manganese complexes for their catalytic activity, versatility to allow multiple transformations and their routes to convert substrates to target molecules. This article will also be helpful to get significant insight into ligand design, thereby aiding catalysis design.

Dual Metalation in a Two-Dimensional Covalent Organic Framework for Photocatalytic C-N Cross-Coupling Reactions.

Covalent organic frameworks (COFs) are promising hosts in heterogeneous catalysis. Herein, we report a dual metalation strategy in a single two-dimensional-COF TpBpy for performing a variety of C-N cross-coupling reactions. [Ir(ppy)2(CH3CN)2]PF6 [ppy = 2-phenylpyridine], containing two labile CH3CN groups, and NiCl2 are used as iridium and nickel-metal precursors, respectively, for postsynthetic decoration of the TpBpy COF. Moving from the traditional approach, we focus on the COF-backbone host for visible-light-mediated nickel-catalyzed C-N coupling reactions. The controlled metalation and recyclability without deactivation of both catalytic centers are unique with respect to previously reported coupling strategies. We performed various photoluminescence, electrochemical, kinetic, and Hammett correlation studies to understand the salient features of the catalyst and reaction mechanism. Furthermore, theoretical calculations delineated the feasibility of electron transfer from the Ir center to the Ni center inside the confined pore of the TpBpy COF. The dual metal anchoring within the COF backbone prevented nickel-black formation. The developed protocol enables selective and reproducible coupling of a diverse range of amines (aryl, heteroaryl, and alkyl), carbamides, and sulfonamides with electron-rich, neutral, and poor (hetero) aryl iodides up to 94% isolated yield. The reaction can also be performed on a gram scale. Furthermore, to establish the practical implementation of this approach, we have applied the synthetic strategy for the late-stage diversification of the derivatives of ibuprofen, naproxen, gemfibrozil, helional, and amino acids. The methodology could also be applied to synthesize pharmacophore N,5-diphenyloxazol-2-amine and Food and Drug Administration-approved drugs, including flufenamic acid, flibanserin, and tripelennamine.

Photoredox/Nickel Dual Catalysis Enables the Synthesis of Alkyl Cyclopropanes via C(sp3)-C(sp3) Cross Electrophile Coupling of Unactivated Alkyl Electrophiles.

A facile synthesis of mono-, 1,1- and 1,2-disubstituted cyclopropanes via visible light-mediated photoredox/nickel dual catalysis is demonstrated. The challenging intramolecular C(sp3)-C(sp3) cross-electrophile coupling of readily available unactivated 1,3-dialkyl electrophiles was performed under mild conditions that allowed traditionally reactive functional groups to be included. Mechanistic inspection and control experiments revealed the importance of dual catalysis and that the reaction proceeds via a stepwise oxidative addition followed by an intramolecular SN2 reaction.

Recent Development of Bis-Cyclometalated Chiral-at-Iridium and Rhodium Complexes for Asymmetric Catalysis.

The field of asymmetric catalysis has been developing to access synthetically efficacious chiral molecules from the last century. Although there are many sustainable ways to produce nonracemic molecules, simplified and unique methodologies are always appreciated. In the recent developments of asymmetric catalysis, chiral-at-metal Lewis acid catalysis has been recognized as an attractive strategy. The catalysts coordinatively activate a substrate while serving the sole source of chirality by virtue of its helical environment. These configurationally stable complexes were utilized in a large number of asymmetric transformations, ranging from asymmetric Lewis acid catalysis to photoredox and electrocatalysis. Here we provide a comprehensive review of the current advancements in asymmetric catalysis utilizing iridium and rhodium-based chiral-at-metal complexes as catalysts. First, the asymmetric transformations via LUMO and HOMO activation assisted by a chiral Lewis acid catalyst are reviewed. In the second part, visible-light-induced asymmetric catalysis is summarized. The asymmetric transformation via the electricity-driven method is discussed in the final section.

Cooperative Lewis Acid Catalysis for the Enantioselective C(sp3)-H Bond Functionalizations of 2-Alkyl Azaarenes.

Herein, we describe the enantioselective C(sp3)-H bond functionalizations of 2-alkyl azaarenes using a cooperative dual Lewis acid catalysis. An achiral Lewis acid activates the unactivated azaarene partner without the need for a strong base. Orthogonally, a chiral-at-metal Lewis acid catalyst enables LUMO lowering and induces chirality. This method tolerates a range of complex molecular scaffolds and exhibits good to excellent yields and selectivity while accepting a wide variety of functional groups.

Advancements in multifunctional manganese complexes for catalytic hydrogen transfer reactions.

Catalytic hydrogen transfer reactions have enormous academic and industrial applications for the production of diverse molecular scaffolds. Over the past few decades, precious late transition-metal catalysts were employed for these reactions. The early transition metals have recently gained much attention due to their lower cost, less toxicity, and overall sustainability. In this regard, manganese, which is the third most abundant transition metal in the Earth's crust, has emerged as a viable alternative. However, the key to the success of such manganese-based complexes lies in the multifunctional ligand design and choice of appropriate ancillary ligands, which helps them mimic and, even in some cases, supersede noble metals' activities. The metal-ligand bifunctionality, achieved via deprotonation of the acidic C-H or N-H bonds, is one of the powerful strategies employed for this purpose. Alongside, the ligand hemilability in which a weakly chelating group tunes in between the coordinated and uncoordinated stages could effectively stabilize the reactive intermediates, thereby facilitating substrate activation and catalysis. Redox non-innocent ligands acting as an electron sink, thereby helping the metal center in steps gaining or losing electrons, and non-classical metal-ligand cooperativity has also played a significant role in the ligand design for manganese catalysis. The strategies were not only employed for the chemoselective hydrogenation of different reducible functionalities but also for the C-X (X = C/N) coupling reactions via HT and downstream cascade processes. This article features multifunctional ligand-based manganese complexes, highlighting the importance of ligand design and choice of ancillary ligands for achieving the desired catalytic activity and selectivity for HT reactions. We have also discussed the detailed reaction pathways for metal complexes involving bifunctionality, hemilability, redox activity, and indirect metal-ligand cooperativity. The synthetic utilization of those complexes in different organic transformations has also been detailed.