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.

Simplifying the Synthesis of Nonproteinogenic Amino Acids via Palladium-Catalyzed δ-Methyl C-H Olefination of Aliphatic Amines and Amino Acids.

Transition metal-catalyzed directing group assisted C-H functionalizations provide a straightforward access to a wide variety of nonproteinogenic amino acids. While altering the side chain of an existing natural amino acids is one way, introducing a functional group to an aliphatic amine to synthesize versatile unnatural amino acids is another exciting avenue. In this work, we explore both the possibilities by the palladium-catalyzed δ-C(sp3)-H olefination of aliphatic amines and amino acids. A diverse substrate scope including sequential difunctionalizations followed by post synthetic transformations were achieved to understand the applicability of the current protocol. An in-depth mechanistic study was carried out to learn the mode of the reaction pathway.

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.

Pd-catalysed C-H functionalisation of free carboxylic acids.

Pd-catalysed C-H functionalisation of free carboxylic acids has drawn significant attention over the last few years due to the predominance of carboxylic acid moieties in pharmaceuticals and agrochemicals. But their coordinating ability was overlooked and masked by exogenous directing groups for a long time. Even other crucial roles of carboxylic acids as additives and steric inducers that directly influence the mode of a reaction have been widely neglected. This review aims to embrace all of the diverse aspects of carboxylic acids except additive and steric effects by concisely and systematically describing their versatile role in Pd-catalysed proximal and distal C-H activation reactions that could be implemented in the pharmaceutical and agrochemical industries. In addition, the mechanistic perspectives along with several recent strategies developed in the last few years discussed here will serve as educational resources for future research.

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.

Hexafluoroisopropanol: the magical solvent for Pd-catalyzed C-H activation.

Among numerous solvents available for chemical transformations, 1,1,1,3,3,3-hexafluoro-2-propanol (popularly known as HFIP) has attracted enough attention of the scientific community in recent years. Several unique features of HFIP compared to its non-fluoro analogue isopropanol have helped this solvent to make a difference in various subdomains of organic chemistry. One such area is transition metal-catalyzed C-H bond functionalization reactions. While, on one side, HFIP is emerging as a green and sustainable deep eutectic solvent (DES), on the other side, a major proportion of Pd-catalyzed C-H functionalization is heavily relying on this solvent. In particular, for distal aromatic C-H functionalizations, the exceptional impact of HFIP to elevate the yield and selectivity has made this solvent irreplaceable. Recent research studies have also highlighted the H-bond-donating ability of HFIP to enhance the chiral induction in Pd-catalyzed atroposelective C-H activation. This perspective aims to portray different shades of HFIP as a magical solvent in Pd-catalyzed C-H functionalization reactions.

Arene diversification through distal C(sp2)-H functionalization.

Transition metal-catalyzed aryl C-H activation is a powerful synthetic tool as it offers step and atom-economical routes to site-selective functionalization. Compared with proximal ortho-C-H activation, distal (meta- and/or para-) C-H activation remains more challenging due to the inaccessibility of these sites in the formation of energetically favorable organometallic pretransition states. Directing the catalyst toward the distal C-H bonds requires judicious template engineering and catalyst design, as well as prudent choice of ligands. This review aims to summarize the recent elegant discoveries exploiting directing group assistance, transient mediators or traceless directors, noncovalent interactions, and catalyst and/or ligand selection to control distal C-H activation.

Transient directing ligands for selective metal-catalysed C-H activation.

C-H activation is a 'simple-to-complex' transformation that nature has perfected over millions of years of evolution. Transition-metal-catalysed C-H activation has emerged as an expeditious means to expand the chemical space by introducing diverse functionalities. Notably, among the strategies to selectively cleave a particular C-H bond, the catalytic use of a small molecule as co-catalyst to generate a transient directing group, which provides a balance between step economy and chemical productivity, has gained immense attention in recent years. This allows one to convert a desired C-H bond irrespective of its geometrical or stereochemical configuration. This Review describes the various transient directing groups used in C-H activation and explains their mechanistic significance.

Para-Selective Cyanation of Arenes by H-Bonded Template.

The significance of site selective functionalization stands upon the superior selectivity, easy synthesis and diverse product utility. In this work, we demonstrate the para-selective introduction of versatile nitrile moiety, enabled by a detachable and reusable H-bonded auxiliary. The methodology holds its efficiency irrespective of substrate electronic bias. The conspicuous shift in the step energetics was probed by both experimental and computational mechanistic tools, which heralds the inception of para-deuteration. The synthetic impact of the methodology was highlighted with reusability of directing group and post synthetic modifications.

H-bonded reusable template assisted para-selective ketonisation using soft electrophilic vinyl ethers.

In nature, enzymatic pathways generate Caryl-C(O) bonds in a site-selective fashion. Synthetically, Caryl-C(O) bonds are synthesised in organometallic reactions using prefunctionalized substrate materials. Electrophilic routes are largely limited to electron-rich systems, non-polar medium, and multiple product formations with a limited scope of general application. Herein we disclose a directed para-selective ketonisation technique of arenes, overriding electronic bias and structural congestion, in the presence of a polar protic solvent. The concept of hard-soft interaction along with in situ activation techniques is utilised to suppress the competitive routes. Mechanistic pathways are investigated both experimentally and computationally to establish the hypothesis. Synthetic utility of the protocol is highlighted in formal synthesis of drugs, drug cores, and bioactive molecules.

Combining transition metals and transient directing groups for C-H functionalizations.

In the domain of synthetic chemistry, C-H bond activation has always remained in the spotlight for researchers over the last few decades. Although different strategies have been employed to chemically trigger unactivated C-H bonds, transition metal catalyzed directing group (DG) aided C-H bond activation is the most explored pathway of all because of its ability to perform diverse site selective functional metamorphosis. Despite its popularity, tedious synthetic methodology requiring additional steps for the installation and removal of DGs from the target substrate diminishes its efficacy. However, replacement of directing groups by transient directing groups (tDGs) reduces the hurdle to a greater extent without compromising the product yield and selectivity. In this report we have depicted the intense journey of transient directing groups with three (Rh, Ru, and Pd) prevalent second row transition metals.