Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C-H Allylation.

The significance of stereoselective C-H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities.

Photoinduced [3+2] Cycloaddition of Carbenes and Nitriles: A Versatile Approach to Oxazole Synthesis.

We have developed a photoinduced protocol for the synthesis of pharmaceutically important oxazole molecules using diazo- and nitrile-containing reactants. The process involves the initial photolysis of the diazo compound to afford singlet carbenes, which are tapped by nitriles in a [3+2] cycloaddition fashion to give substituted oxazoles. With di-nitrile compounds, useful bis-oxazoles were obtained. The applicability of the transformation is showcased through the expedient synthesis of small-molecule drugs and biologically relevant molecules such as felbinac, pimprinine, texamine, ugnenenazole etc. The protocol is also useful for the generation of 2 H and 13 C isotope labelled oxazoles. Merging photolysis with continuous-flow chemistry was demonstrated for scaling up the reaction. The non-requirement of metal catalysis or photosensitizers to harness the light energy with blue light sufficing the execution of the reaction makes it a versatile and general protocol for the synthesis of structurally diverse oxazoles.

Unveiling catalyst-free electro-photochemical reactivity of aryl diazoesters and facile synthesis of oxazoles, imide-fused pyrroles and tetrahydro-epoxy-pyridines via carbene radical anions.

Herein, we report a reagent-less (devoid of catalyst, supporting electrolyte, oxidant and reductant) electro-photochemical (EPC) reaction [electricity (50 µA) and blue LED (5 W)] of aryl diazoesters to generate radical anions which are subsequently reacted with acetonitrile or propionitrile and maleimides to generate diversely substituted oxazoles, diastereo-selective imide-fused pyrroles and tetrahydroepoxy-pyridines in good to excellent yield. Thorough mechanistic investigation including a 'biphasic e-cell' experiment supports the reaction mechanism involving a carbene radical anion. The tetrahydroepoxy-pyridines could be fluently converted to fused pyridines resembling vitamin B6 derivatives. The source of the electric current in the EPC reaction could be a simple cell phone charger. The reaction was efficiently scaled up to the gram level. Crystal structure, 1D, 2D NMRs and HRMS data confirmed the product structures. This report demonstrates a unique generation of radical anions via electro-photochemistry and their direct applications in the synthesis of important heterocycles.

Substrate-Rhodium Cooperativity in Photoinduced ortho-Alkynylation of Arenes.

In the realm of metallaphotocatalytic C-H activation strategy, the direct excitation of the transition metal which plays the dual role of light energy harnessing alongside performing the bond breaking and forming is a rare phenomenon. In this context we have developed the first photo-induced Rh-catalyzed ortho-alkynylation under ambient conditions without the requirement of silver salt, photocatalyst (PC) or any engineered substrate or catalyst. The transformation functions by the specific cooperative effect of a six-membered rhodacycle which is the photo-responsive species. The catalytic system allows the conjugation of arenes with sp3 -rich pharmacophoric fragments. The control experiments as well as the computational studies resolve the mechanistic intricacies for this transformation. An outer sphere electron transfer process from Rh to alkynyl radical is operative for the present photo-induced transformation over the more common oxidative addition or 1,2-migratory insertion pathways.

Expanding chemical space by para-C-H arylation of arenes.

Biaryl scaffolds are privileged templates used in the discovery and design of therapeutics with high affinity and specificity for a broad range of protein targets. Biaryls are found in the structures of therapeutics, including antibiotics, anti-inflammatory, analgesic, neurological and antihypertensive drugs. However, existing synthetic routes to biphenyls rely on traditional coupling approaches that require both arenes to be prefunctionalized with halides or pseudohalides with the desired regiochemistry. Therefore, the coupling of drug fragments may be challenging via conventional approaches. As an attractive alternative, directed C-H activation has the potential to be a versatile tool to form para-substituted biphenyl motifs selectively. However, existing C-H arylation protocols are not suitable for drug entities as they are hindered by catalyst deactivation by polar and delicate functionalities present alongside the instability of macrocyclic intermediates required for para-C-H activation. To address this challenge, we have developed a robust catalytic system that displays unique efficacy towards para-arylation of highly functionalized substrates such as drug entities, giving access to structurally diversified biaryl scaffolds. This diversification process provides access to an expanded chemical space for further exploration in drug discovery. Further, the applicability of the transformation is realized through the synthesis of drug molecules bearing a biphenyl fragment. Computational and experimental mechanistic studies further provide insight into the catalytic cycle operative in this versatile C-H arylation protocol.

Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites.

The Fujiwara-Moritani reaction has had a profound contribution in the emergence of contemporary C-H activation protocols. Despite the applicability of the traditional approach in different fields, the associated reactivity and regioselectivity issues had rendered it redundant. The revival of this exemplary reaction requires the development of a mechanistic paradigm that would have simultaneous control on both the reactivity and regioselectivity. Often, the high thermal energy required to promote olefination leads to multiple site functionalizations. To this aim, we established a photoredox catalytic system constituting a merger of palladium/organo-photocatalyst (PC) that forges oxidative olefination in an explicit regioselective fashion with diverse arenes and heteroarenes. Visible light plays a significant role in executing "regioresolved" Fujiwara-Moritani reactions without the requirement of silver salts and thermal energy. The catalytic system is also amenable toward proximal and distal olefination aided by the respective directing groups (DGs), which entails the versatility of the protocol in engaging the entire spectrum of C(sp2)-H olefination. Furthermore, streamlining the synthesis of natural products, chiral molecules, drugs, and diversification through late-stage functionalizations underscore the importance of this sustainable protocol. The photoinduced attainment of this regioselective transformation is mechanistically established through control reactions and kinetic studies.

Toolbox for Distal C-H Bond Functionalizations in Organic Molecules.

Transition-metal-catalyzed C-H activation has developed a contemporary approach to the omnipresent area of retrosynthetic disconnection. Scientific researchers have been tempted to take the help of this methodology to plan their synthetic discourses. This paradigm shift has helped in the development of industrial units as well, making the synthesis of natural products and pharmaceutical drugs step-economical. In the vast zone of C-H bond activation, the functionalization of proximal C-H bonds has gained utmost popularity. Unlike the activation of proximal C-H bonds, the distal C-H functionalization is more strenuous and requires distinctly specialized techniques. In this review, we have compiled various methods adopted to functionalize distal C-H bonds, mechanistic insights within each of these procedures, and the scope of the methodology. With this review, we give a complete overview of the expeditious progress the distal C-H activation has made in the field of synthetic organic chemistry while also highlighting its pitfalls, thus leaving the field open for further synthetic modifications.

Ligand-Enabled δ-C(sp3 )-H Borylation of Aliphatic Amines.

Directed C-H functionalization has been realized as a complimentary technique to achieve borylation at a distal position of aliphatic amines. Here, we demonstrated the oxidative borylation at the distal δ-position of aliphatic amines using various borylating agents, a palladium catalyst, and a rightly tuned ligand in the presence of a cheap oxidant. Moreover, an organopalladium δ-C(sp3 )-H-activated intermediate has been isolated and crystallographically characterized to get mechanistic insight.

Alkyne Linchpin Strategy for Drug:Pharmacophore Conjugation: Experimental and Computational Realization of a Meta-Selective Inverse Sonogashira Coupling.

The late-stage functionalization (LSF) of pharmaceutical and agrochemical compounds by the site-selective activation of C-H bonds provides access to diverse structural analogs and expands synthetically-accessible chemical space. We report a C-H functionalization LSF strategy that hinges on the use of an alkyne linchpin to assemble conjugates of sp2-rich marketed pharmaceuticals and agrochemicals with sp3-rich 3D fragments and natural products. This is accomplished through a template-assisted inverse Sonogashira reaction that displays high levels of selectivity for the meta position. This protocol is also amenable to distal structural modifications of α-amino acids. The transformation of alkyne functionality to other functional groups further highlights the applicative potential. Computational and experimental mechanistic studies shed light on the detailed mechanism. Turnover-limiting 1,2-migratory insertion of the bromoalkyne coupling partner occurs after relatively fast C-H activation. While this insertion occurs unselectively, regioconvergence results from one of the adducts undergoing a 1,2-trialkylsilyl migration to form the alkynylated product. A heterobimetallic Pd-Ag transition structure is essential for product formation in the ß-bromide elimination step.

Diverse strategies for transition metal catalyzed distal C(sp3)-H functionalizations.

Transition metal catalyzed C(sp3)-H functionalization is a rapidly growing field. Despite severe challenges, distal C-H functionalizations of aliphatic molecules by overriding proximal positions have witnessed tremendous progress. While usage of stoichiometric directing groups played a crucial role, reactions with catalytic transient directing groups or methods without any directing groups are gaining more attention due to their practicality. Various innovative strategies, slowly but steadily, circumvented issues related to remote functionalizations of aliphatic molecules. A systematic compilation has been presented here to provide insights into the recent developments and future challenges in the field. The Present perspective is expected to open up a new dimension and provide an avenue for deep insights into the distal C(sp3)-H functionalizations that could be applied routinely in various pharmaceutical and agrochemical industries.

Iterative Arylation of Amino Acids and Aliphatic Amines via δ-C(sp3 )-H Activation: Experimental and Computational Exploration.

Directed C-H functionalization has been realized as a complementary tool to the traditional approaches for a straightforward access of non-proteinogenic amino acids; albeit such a process is restricted mostly up to the γ-position. In the present work, we demonstrate the diverse (hetero)arylation of amino acids and analogous aliphatic amines selectively at the remote δ-position by tuning the reactivity controlled by ligands. An organopalladium δ-C(sp3 )-H activated intermediate has been isolated and crystallographically characterized. Mechanistic investigations carried out experimentally in conjunction with computational studies shed light on the difference in the mechanistic picture depending on the substrate structure.

Experimental and Computational Exploration of para-Selective Silylation with a Hydrogen-Bonded Template.

The regioselective conversion of C-H bonds into C-Si bonds is extremely important owing to the natural abundance and non-toxicity of silicon. Classical silylation reactions often suffer from poor functional group compatibility, low atom economy, and insufficient regioselectivity. Herein, we disclose a template-assisted method for the regioselective para silylation of toluene derivatives. A new template was designed, and the origin of selectivity was analyzed experimentally and computationally. An interesting substrate-solvent hydrogen-bonding interaction was observed. Kinetic, spectroscopic, and computational studies shed light on the reaction mechanism. The synthetic significance of this strategy was highlighted by the generation of a precursor of a potential lipophilic bioisostere of γ-aminobutyric acid (GABA), various late-stage diversifications, and by mimicking enzymatic transformations.

Synthesis of esters via sp(3) C-H functionalisation.

Oxidative C-O bond formation via sp(3) C-H functionalisation represents an attractive approach for the synthesis of esters. This review focuses on the recent advances of sp(3) C-H bond functionalisation strategies for ester synthesis from unconventional precursors using transition metal/metal free catalysts in combination with various oxidants. Various classes of esters and the mechanisms of their formation are discussed with numerous examples.

Synthesis of 1,2,4-Triazoles via Oxidative Heterocyclization: Selective C-N Bond Over C-S Bond Formation.

The higher propensity of C-N over C-S bond forming ability was demonstrated, through formal C-H functionalization during the construction of 4,5-disubstituted 1,2,4-triazole-3-thiones from arylidenearylthiosemicarbazides catalyzed by Cu(II). However, steric factors imparted by the o-disubstituted substrates tend to change the reaction path giving thiodiazole as the major or an exclusive product. Upon prolonging the reaction time, the in situ generated thiones are transformed to 4,5-disubstituted 1,2,4-triazoles via a desulfurization process. Two classes of heterocycles viz. 4,5-disubstituted 1,2,4-triazole-3-thiones and 4,5-disubstituted 1,2,4-triazoles can be synthesized from arylidenearylthiosemicarbazides by simply adjusting the reaction time. Desulfurization of 1,2,4-triazole-3-thiones is assisted by thiophilic Cu to provide 1,2,4-triazoles with concomitant formation of CuS and polynuclear sulfur anions as confirmed from scanning electron microscope and energy dispersive X-ray spectroscopy measurements. A one-pot synthesis of an antimicrobial compound has been successfully achieved following this strategy.

Regiospecific Benzoylation of Electron-Deficient N-Heterocycles with Methylbenzenes via a Minisci-Type Reaction.

A regioselective cross-dehydrogenative coupling between electron-deficient N-heterocycles (isoquinoline, quinolines, and quinoxalines) and methylbenzenes leading to regiospecific C-aroylation has been accomplished using AlCl3 as the catalyst in the presence of oxidant TBHP. This protocol is a practical alternative to the classical Minisci reaction.

Cyclic ethers to esters and monoesters to bis-esters with unconventional coupling partners under metal free conditions via sp(3) C-H functionalisation.

An efficient metal free oxidative esterification of sp(3) C-H bonds (adjacent to an oxygen atom) in simple solvents like 1,4-dioxane, tetrahydropyran, tetrahydrofuran and ethyl acetate has been achieved using terminal aryl alkenes and alkynes as the ArCOO(-) sources.

A metal free domino synthesis of 3-aroylindoles via two sp³ C-H activation.

A metal free synthesis of 3-aroylindole involving two sp(3) C-H activation has been achieved starting from o-alkynyl-N,N-dialkylamines using catalyst TBAI and oxidant TBHP.

Copper-catalyzed esterification of alkylbenzenes with cyclic ethers and cycloalkanes via C(sp3)-H activation following cross-dehydrogenative coupling.

A copper-catalyzed cross-dehydrogenative coupling strategy has been developed for the synthesis of two classes of esters from simple solvents. The reaction of methylarenes with cyclic ethers resulted in α-acyloxy ethers involving four sp(3) C-H cleavages, while treatment of methylarenes with cycloalkanes led to the formation of allyl esters at the expense of six consecutive sp(3) C-H bonds.