Abstract:Direct para-selective C−H functionalization of arenes remains a daunting challenge and is still significantly restricted to a few scaffolds. Herein, we report an unprecedented pyridine-based para-directing template (DT) assisted, Pd-catalyzed...
“…This strategy is also not amenable to introducing heteroarene moieties, severely limiting its applicability in the preparation of pharmaceutically relevant fragments and drugs. Thus, the development of a general catalytic system is needed in which (i) the directing group (DG) outcompetes other Lewis basic atoms to bind the catalyst, and (ii) in which a stable macrocyclic intermediate required for DG-enabled para -C−H activation can be accessed 31 – 35 . Fig.…”
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.
“…This strategy is also not amenable to introducing heteroarene moieties, severely limiting its applicability in the preparation of pharmaceutically relevant fragments and drugs. Thus, the development of a general catalytic system is needed in which (i) the directing group (DG) outcompetes other Lewis basic atoms to bind the catalyst, and (ii) in which a stable macrocyclic intermediate required for DG-enabled para -C−H activation can be accessed 31 – 35 . Fig.…”
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.
“…To date, 13 unique substrate-DT scaffolds has been reportedonly 6 of which are highly selective. Of note, studies toward the DT-mediated functionalization of electronically unbiased substrates are especially scant. ,, Analysis of published DTscaveated by their small sample sizeindicated that para -selective DTs possessed a higher geometric score (DT score = 6) and optimal MCP distance (MCP = 16). In addition, we observed that all published para DTs tended to possess at least two aromatic rings in the linker (which accounts for least six atoms within the MCP) for optimal DG positioning. ,, Due to structural constraints imposed by these linker designs, only a limited class of phenyl substratesspecifically benzyl and phenethyl-containing scaffoldshave been successfully employed for para functionalization.…”
Section: Resultsmentioning
confidence: 99%
“…Of note, studies toward the DT-mediated functionalization of electronically unbiased substrates are especially scant. ,, Analysis of published DTscaveated by their small sample sizeindicated that para -selective DTs possessed a higher geometric score (DT score = 6) and optimal MCP distance (MCP = 16). In addition, we observed that all published para DTs tended to possess at least two aromatic rings in the linker (which accounts for least six atoms within the MCP) for optimal DG positioning. ,, Due to structural constraints imposed by these linker designs, only a limited class of phenyl substratesspecifically benzyl and phenethyl-containing scaffoldshave been successfully employed for para functionalization. Given the low sample size and high degree of structural similarity between most reported para -selective DTs, we wanted to experimentally validate the factors that drive para regioselection and explore the generality of our obtained insights.…”
Section: Resultsmentioning
confidence: 99%
“…To examine our longstanding hypothesis that simple spatial factors, that is, template distance and geometry, are sufficient to tune catalyst positioning, and therefore able to capture the selectivity of a remote DT, we undertook a systematic analysis of 119 structurally unique published ortho , − meta , ,,− and para -DTs − published between 2012 and 2021. We report herein, in this hybrid literature analysis/research article, the key factors that were found to be particularly determinant for selectivity in DT-mediated remote arene C–H activation.…”
The ability to differentiate and selectively activate remote C−H bonds represents a perennial challenge in the field of C−H activation. Since its first report in 2012, a now-established "directing template" (DT) approach remains demonstrably effective for the functionalization of remote C−H bonds. As selectivity is hypothesized to be principally determined by the optimal positioning of the reactive catalyst to a target C−H bond, a DT's spatial factors are particularly important toward achieving high selectivity, though a systematic study on its requisite factors remain unelucidated. Through an in-depth analysis of 119 structurally unique published remote DTs, this report summarizes the key factors that are central toward achieving high selectivity at defined aryl positions, which are experimentally corroborated through the development of new aliphatic meta and para-selective DTs for electronically unbiased arenes. These empirical rules, which summarize key distance and geometric factors, are expected to be useful tools for the future development of site-selective arene C−H activation as well as other reactions that rely on covalent/noncovalent DT-mediated remote regioselection.
“…To render the catalyst proximal to the distal C–H bond efficiently, the C–H activation process frequently requires the participation of a deliberated σ-bonding directing group (DG) in the formation of a metal-embedded macrocyclic transition state. However, the stoichiometric installation and removal of a DG consistently influence the synthetic efficacy of the C–H functionalization strategy. , Moreover, some kinds of substrates such as aromatic aldehydes/ketones and esters, among others, are incompatible with the DG’s methodology because they lack a site for the installation of DG. In contrast, the employment of noncovalent bonding interactions to direct transition-metal-catalyzed C–H functionalization remarkably solves these irreconcilable conflicts.…”
Controlling positional selectivity
represents one of the most important
aspects in transition-metal-catalyzed C–H bond functionalization.
However, the conventional directing template strategies via a covalent
binding to the substrates are always hindered by prior stoichiometric
installation and removal of the directing groups. Herein, we report
a palladium-catalyzed meta-selective C–H olefination
of aromatic carbonyl compounds by noncovalent hydrogen-bonding interaction.
N,N′-Substituted ureas were engineered to serve as a H-bonding
donor for binding to the substrates and, meanwhile, achieve site-selective
control by the integrated directing group.
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