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

Abstract

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.

The Renaissance of Organo Nitriles in Organic Synthesis

“…In 2022, Maiti and co-workers developed a Pd(II)-catalyzed para-CÀ H arylation of substituted arenes (9) using aryl iodides (10) as coupling partners for the synthesis of biaryl compounds (11) (Scheme 4). [8] The transformation uses a removable Ushaped nitrile template T 2 , mono-protected amino acid N-Fmoc-Gly-OH as a ligand, in combination with Ag 2 SO 4 , Cu 2 Cr 2 O 5 , and LiOAc • 2H 2 O. The protocol is amenable to a range of functionalities present in both arenes and aryl iodides, irrespective of their orientation.…”

Remote-Group-Assisted Facile Oxidative Arylation of Furans and Pyrroles

“…Remote groups and directing templates are pivotal transformative tools in transition-metal-catalyzed, especially palladium-catalyzed, C sp2 -H arylation of arenes and heteroarenes . These groups can override the intrinsic electrical and steric properties of the arene substrates to precisely control positional selectivity via stabilizing the macrocyclic organometallic intermediate in the pretransition state .…”

Cross-Coupling versus Homo-Coupling at a Pt(IV) Center: Computational and Experimental Approaches

“…Reductive elimination (RE) reactions are part of important catalytic processes. − RE with concomitant C–C cross-coupling plays a key role in the synthesis of organic molecules, including natural products and drugs. − RE from organometallic d 6 -configured octahedral Pt­(IV) and Pd­(IV) complexes with the concomitant formation of alkanes by Csp 3 –Csp 3 cross-coupling has been extensively studied, − while investigations on homo-coupling reactions are scarce. − …”