Deuteration and Tritiation of Pharmaceuticals by Non-Directed Palladium-Catalyzed C-H Activation in Heavy and Super-Heavy Water.

Deuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non-directed homogeneous Pd-catalysis. Aromatic C-H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D2O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non-directed homogeneous Pd-catalysis for H/T exchange on three different pharmaceuticals by using T2O as isotopic source, demonstrating the applicability to the synthesis of radiotracers.

Dual Ligand Enabled Nondirected C-H Chalcogenation of Arenes and Heteroarenes.

Chalcogenide motifs are present as principal moieties in a vast array of natural products and complex molecules. Till date, the construction of these chalcogen motifs has been restricted to either the use of directing groups or the employment of a large excess of electronically activated arenes, typically employed as a cosolvent. Despite being highly effective, these methods have their own limitations in the step economy and the deployment of an excess amount of arenes. Herein, we report the evolution of a catalytic system employing arene-limited, nondirected thioarylation of arenes and heteroarenes using a complimentary dual-ligand approach. The reaction is controlled by a combination of steric and electronic factors, and the utilization of a suitable ligand enables the generation of products on a complimentary spectrum to that generated by classical methods. The combination of ligands remains imperative in the reaction protocol with theoretical calculations pointing towards a monoprotected amino acid ligand being crucial in the concerted metalation deprotonation (CMD) mechanism by a characteristic [5,6]-palladacyclic transition state, while the pyridine moiety assists in the active catalyst species formation and product release. Combined experimental and computational mechanistic investigations point toward the C-H activation step being both regio- and rate-determining. Interestingly, oxidative addition of the diphenyl disulfide substrate is found to be unlikely, and an alternative transmetalation-like mechanism involving the Pd-Ag heterometallic complex is proposed to be operative.

para-Selective Arylation of Arenes: A Direct Route to Biaryls by Norbornene Relay Palladation.

Biaryl compounds are extremely important structural motifs in natural products, biologically active components and pharmaceuticals. Selective synthesis of biaryls by distinguishing the subtle reactivity difference of distal arene C-H bonds are significantly challenging. Herein, we describe para-selective C-H arylation, which is acheived by a unique combination of a meta-directing group and norbornene as a transient mediator. Upon direct meta-C-H palladation, one-bond relay palladation occurs in presence of norbornene and subsequently para-C-H arylation is achieved for sulfonates, phosphonates and phenols bearing 2,6-disubstitution patterns. The protocol is amenable to electron-deficient aryl iodides. Multisubstituted arenes and phenols are obtained by postsynthetic modification of the products. The protocol allows the synthesis of hexa-substituted benzene by sequential selective distal C-H functionalization.

Base Metal Catalyst for Indirect Hydrogenation of CO2.

We herein report a novel Mn-SNS-based catalyst, which is capable of performing indirect hydrogenation of CO2 to methanol via formylation. In this domain of CO2 hydrogenation, pincer ligands have shown a clear predominance. Our catalyst is based on the SNS-type tridentate ligand, which is quite stable and cheap as compared to the pincer type ligands. The catalyst can also be recycled effectively after the formylation reaction without any significant change in efficiency. Various amines including both primary and secondary amines worked well under the protocol to provide the desired formylated product in good yields. The formed formylated amines can also be reduced further at higher pressures of hydrogen. As a whole, we have developed a protocol that involves indirect CO2 hydrogenation to methanol that proceeds via formylation of amines.

Traditional and sustainable approaches for the construction of C-C bonds by harnessing C-H arylation.

Biaryl scaffolds are found in natural products and drug molecules and exhibit a wide range of biological activities. In past decade, the transition metal-catalyzed C-H arylation reaction came out as an effective tool for the construction of biaryl motifs. However, traditional transition metal-catalyzed C-H arylation reactions have limitations like harsh reaction conditions, narrow substrate scope, use of additives etc. and therefore encouraged synthetic chemists to look for alternate greener approaches. This review aims to draw a general overview on C-H bond arylation reactions for the formation of C-C bonds with the aid of different methodologies, majorly highlighting on greener and sustainable approaches.

Recent developments in first-row transition metal complex-catalyzed CO2 hydrogenation.

Our modern civilization is currently standing at a crossroads due to excessive emission of anthropogenic CO2 leading to adverse climate change effects. Hence, a proper CO2 management strategy, including appropriate CO2 capture, utilization, and storage (CCUS), has become a prime concern globally. On the other hand, C1 chemicals such as methanol (CH3OH) and formic acid (HCOOH) have emerged as leading materials for a wide range of applications in various industries, including chemical, biochemical, pharmaceutical, agrochemical, and even energy sectors. Hence, there is a concerted effort to bridge the gap between CO2 management and methanol/formic acid production by employing CO2 as a C1-synthon. CO2 hydrogenation to methanol and formic acid has emerged as one of the primary routes for directly converting CO2 to a copious amount of methanol and formate, which is typically catalyzed by transition metal complexes. In this frontier article, we have primarily discussed the abundant first-row transition metal-driven hydrogenation reaction that has exhibited a significant surge in activity over the past few years. We have also highlighted the potential future direction of the research while incorporating a comparative analysis for the competitive second and third-row transition metal-based hydrogenation.

Non-directed Pd-catalysed electrooxidative olefination of arenes.

The Fujiwara-Moritani reaction is a powerful tool for the olefination of arenes by Pd-catalysed C-H activation. However, the need for superstoichiometric amounts of toxic chemical oxidants makes the reaction unattractive from an environmental and atom-economical view. Herein, we report the first non-directed and regioselective olefination of simple arenes via an electrooxidative Fujiwara-Moritani reaction. The versatility of this operator-friendly approach was demonstrated by a broad substrate scope which includes arenes, heteroarenes and a variety of olefins. Electroanalytical studies suggest the involvement of a Pd(ii)/Pd(iv) catalytic cycle via a Pd(iii) intermediate.