Breakthrough in C-H Activation Catalyst Technology

September 12, 2024 - Johnson Matthey Catalysis & Chiral Technologies announces a significant breakthrough in C-H activation catalyst technology with the development of novel iridium complexes that enable highly selective C-H borylation at previously inaccessible molecular positions. This advancement dramatically expands the synthetic toolkit available to pharmaceutical chemists for late-stage functionalization and complex molecule synthesis.

Transforming C-H Bonds into Functional Groups

Carbon-hydrogen bonds are ubiquitous in organic molecules, yet traditional synthesis largely treats them as inert spectators. Selective functionalization of specific C-H bonds offers powerful advantages by eliminating protection-deprotection sequences, reducing step counts, and enabling disconnections impossible through conventional approaches. However, achieving selectivity among multiple similar C-H bonds in complex molecules has remained a fundamental challenge.

C-H borylation represents a particularly valuable transformation because organoboron products undergo diverse downstream functionalizations. Boronic esters can be converted to alcohols, amines, halides, or coupled with aryl halides through Suzuki reactions. This versatility makes C-H borylation a strategic gateway to molecular complexity.

Existing C-H borylation catalysts predominantly functionalize sterically accessible positions, with selectivity governed primarily by substrate steric features. While useful, this limitation restricts application to molecules where the desired functionalization site happens to be the least hindered position. Many pharmaceutical targets require functionalization at sterically congested positions adjacent to functional groups or heteroatoms.

Mechanistic Innovation

Our breakthrough catalysts employ iridium metal centers paired with specially designed N-heterocyclic carbene ligands that create unique steric and electronic environments. Unlike conventional phosphine-ligated iridium catalysts, the NHC systems exhibit altered site selectivity patterns governed by electronic substrate features in addition to sterics.

Mechanistic studies combining experimental kinetics and computational modeling revealed that the NHC ligands modify the catalyst’s preference for C-H bond oxidative addition. Traditional catalysts preferentially activate the most accessible C-H bonds. Our modified catalysts show enhanced reactivity toward C-H bonds adjacent to heteroatoms and π-systems, even when these positions are sterically hindered.

This electronic bias arises from specific orbital interactions between the substrate C-H bonds and the iridium-NHC catalyst. Computational analysis identified how the carbene ligand’s electronic properties influence the metal center’s frontier orbitals, making it more receptive to interaction with polarized C-H bonds near electron-withdrawing groups.

The mechanistic insight enabled rational optimization of ligand structure. We synthesized a focused library of NHC variants with systematic electronic and steric property variations. Structure-activity relationships identified the optimal balance of properties for different substrate classes. Some ligands favor benzylic C-H activation adjacent to nitrogen heterocycles, while others preferentially activate aliphatic C-H bonds alpha to ketones.

Substrate Scope Expansion

Comprehensive substrate scope studies demonstrate the catalysts’ ability to address previously challenging transformations. Heterocyclic drug scaffolds including pyridines, quinolines, indoles, and pyrimidines undergo selective borylation at positions difficult to access through traditional methods. This capability is particularly valuable for pharmaceutical applications where heterocycles are prevalent.

Selective functionalization of complex natural product derivatives illustrates the catalysts’ potential for late-stage diversification. Many pharmaceutical programs begin with naturally occurring compounds as lead structures, then seek to improve properties through structural modifications. Late-stage C-H functionalization enables introduction of groups at positions that would be difficult to install through traditional total synthesis.

Aliphatic C-H borylation, historically more challenging than aromatic C-H activation, proceeds efficiently with our catalyst systems. Primary, secondary, and tertiary C-H bonds can all be borylated with appropriate catalyst-ligand combinations. Site selectivity follows predictable patterns based on C-H bond polarity and steric accessibility.

Functional group tolerance testing revealed excellent compatibility with pharmaceutical-relevant functionality. Esters, ketones, amides, carbamates, sulfonamides, and unprotected alcohols and amines all survive the reaction conditions. This broad tolerance eliminates protecting group requirements and enables application to advanced intermediates.

Regioselectivity Control

A particularly powerful feature of the new catalysts is tunable regioselectivity through ligand selection. For substrates containing multiple potentially reactive C-H bonds, different ligands can direct borylation to different positions. This programmable selectivity enables access to multiple regioisomeric products from a single substrate.

We demonstrated this capability with several drug molecules, showing how ligand variation provides complementary borylated products. For instance, a quinoline-containing pharmaceutical underwent borylation at the 6-position with one catalyst but at the 3-position with an alternative ligand. Both products were obtained in high yield and selectivity, illustrating how catalyst choice determines outcome.

Mechanistic understanding of selectivity determinants enables prediction of optimal catalyst-substrate matching. Computational screening of catalyst-substrate combinations identifies promising candidates for experimental validation. This predictive capability accelerates application development by reducing experimental trial-and-error.

Process Development and Scale-Up

Laboratory-scale success requires translation to practical processes suitable for pharmaceutical manufacturing. We invested significant effort in developing robust procedures amenable to scale-up. Key challenges included air and moisture sensitivity of catalyst components, requirement for rigorously dry solvents, and handling of diboron reagents.

Catalyst stability studies identified formulation improvements that enhance shelf life and ease of handling. Pre-formed iridium-NHC complexes, isolated as air-stable solids, eliminate the need for in situ catalyst generation from sensitive precursors. These materials can be weighed in air and provide consistent performance across batches.

Solvent screening identified greener alternatives to traditional ethereal solvents like tetrahydrofuran. Methyl tetrahydrofuran, derived from renewable feedstocks, provides equivalent performance with improved environmental profile. We also demonstrated aqueous workup procedures that simplify product isolation compared to traditional chromatographic purification.

Kilogram-scale demonstrations validated the practical viability of the methodology. A pharmaceutical partner employed our catalyst for multi-kilogram synthesis of a borylated drug intermediate, achieving yields and selectivities matching laboratory results. Process safety reviews confirmed the approach meets pharmaceutical manufacturing standards with appropriate controls.

Computational Catalyst Design Tools

The mechanistic insights gained during this research enabled development of computational tools for catalyst design and optimization. Machine learning models trained on our experimental dataset predict catalyst performance for new substrates without requiring synthesis and testing of all possible combinations.

These predictive models dramatically accelerate application development. When customers present challenging substrates, we computationally screen our catalyst library to identify the most promising candidates. Experimental validation then focuses on the top computational predictions, reducing time and resource requirements.

The models continue learning as we accumulate additional experimental data, progressively improving prediction accuracy. This virtuous cycle of experimentation informing computation, which guides further experimentation, accelerates our catalyst development capabilities.

Intellectual Property and Publications

This research generated substantial intellectual property now protected through patent applications filed in major pharmaceutical markets. The patent portfolio covers the novel catalyst compositions, their synthesis, and application to pharmaceutical intermediate synthesis. We retain freedom to operate while the patents protect our innovations from direct copying.

We are committed to advancing scientific knowledge through peer-reviewed publication. A full research article describing the catalyst development, mechanistic studies, and substrate scope is in press at a leading chemistry journal. Additional publications detailing specific applications are in preparation.

Presenting our work at scientific conferences facilitates knowledge exchange with the broader research community. Our scientists have delivered invited lectures at major catalysis conferences including the North American Catalysis Society Meeting and the International Conference on Organometallic Chemistry. These presentations generate valuable feedback and potential collaboration opportunities.

Commercial Availability

The breakthrough catalysts are now available for customer evaluation. We offer a starter kit containing representative catalysts spanning the performance range of the family. The kit includes sufficient material for reaction screening and optimization, along with detailed protocols for catalyst use.

Custom catalyst selection support is available for customers with specific substrate challenges. Our technical team can computationally screen catalyst candidates and recommend optimal choices for experimental validation. Follow-up consultation helps optimize reaction conditions for customer-specific applications.

Manufacturing-scale catalyst supply leverages our global production network. Catalyst synthesis has been transferred to our production facilities, enabling supply from laboratory quantities through commercial scale. We maintain inventory of the most commonly requested variants to ensure rapid delivery.

Customer Applications

Early customer adopters have reported impressive results applying our C-H borylation catalysts to pharmaceutical synthesis challenges. A kinase inhibitor program utilized the technology for late-stage diversification, generating a library of analogs for structure-activity relationship studies. The ability to install boronic ester handles at diverse positions enabled exploration of chemical space difficult to access through traditional synthesis.

A neuroscience drug discovery program employed the catalysts to prepare isotopically labeled tracers for positron emission tomography imaging studies. Site-selective deuteration through C-H activation followed by deuterium-tritium exchange provided specifically labeled compounds for metabolic studies. This application demonstrates the technology’s utility beyond traditional synthesis applications.

Generic pharmaceutical manufacturers see potential for the technology in developing alternative synthetic routes to branded drugs. C-H activation-based routes can offer advantages in step count, yield, or intellectual property position compared to literature procedures. Several companies are actively exploring these opportunities.

Future Development

Research continues on expanding C-H activation capabilities to additional transformation types beyond borylation. C-H silylation, amination, and alkylation represent high-priority targets. Some preliminary results with modified catalyst systems show promise for these transformations.

Asymmetric C-H activation to generate chiral centers directly from prochiral substrates represents a long-term goal. While highly challenging, success would provide transformative synthetic capabilities. Our academic partnerships include focused efforts on developing chiral versions of our catalyst systems.

We remain committed to advancing C-H activation from a specialized research tool to a mainstream pharmaceutical synthesis methodology. The breakthrough catalysts announced today represent an important step toward that vision. We look forward to collaborating with pharmaceutical chemists to apply these powerful new catalytic capabilities to their most challenging synthesis problems.