A photoredox and transition metal catalysis platform for N-functionalization of sulfoximines with diverse groups

Background

Sulfoximines have emerged as valuable motifs in medicinal chemistry due to their unique bioisosteric properties, chemical stability, and potential to enhance the pharmacological profiles of drug candidates. Their incorporation into pharmaceuticals can improve solubility, metabolic stability, and modulate acidity, making them attractive for drug design. As a result, there is growing interest in methods that enable the efficient and selective functionalization of sulfoximines, particularly at the nitrogen atom, to introduce diverse alkyl and aryl groups. Such modifications are crucial for exploring new chemical space and optimizing the biological activity of lead compounds in drug discovery.

Despite their promise, existing approaches for N-functionalization of sulfoximines are fraught with significant limitations. Traditional N-arylation methods often rely on palladium-catalyzed cross-coupling reactions, which are inefficient when applied to complex or heteroaromatic substrates and can be incompatible with sensitive functional groups. N-alkylation strategies are even more restrictive, typically limited to simple methylation and frequently requiring hazardous or explosive reagents, thus posing safety and scalability concerns. Furthermore, these methods offer poor yields, limited substrate scope, and lack the generality needed for late-stage functionalization of complex, drug-like molecules. Consequently, there is a pressing need for new, broadly applicable, and safe methodologies that can reliably introduce a wide range of alkyl and aryl groups onto sulfoximines under mild conditions.

Technology

This technology enables the efficient N-alkylation and N-arylation of sulfoximines by leveraging transition metal-catalyzed radical capture and reductive elimination, facilitated by visible-light photoredox catalysis. The process begins with the coordination of a sulfoximine to a transition metal, such as copper, forming an amido complex. Under mild conditions, alkyl radicals are generated from N-heterocyclic carbene-alcohol adducts or aryl radicals from aryl halides via halogen abstraction, both initiated by a photocatalyst under visible light. These reactive radicals are intercepted by the metal-amido complex, leading to a high-valent intermediate that undergoes reductive elimination to yield the desired N-functionalized sulfoximine. The methodology accommodates a wide variety of starting materials, including aliphatic alcohols and aryl halides, and is compatible with complex pharmaceutical scaffolds and diverse functional groups.

What differentiates this technology is its broad substrate scope, operational simplicity, and safety compared to traditional methods. Unlike conventional approaches that often require hazardous reagents, harsh conditions, or are limited to simple methylation or inefficient arylation, this solution employs benign, readily available starting materials and avoids explosive or toxic reagents. The use of visible-light photoredox catalysis allows for mild reaction conditions, preserving sensitive functional groups and enabling late-stage functionalization of drug-like molecules. Additionally, the process demonstrates high configurational stability and functional group tolerance, making it particularly valuable for medicinal chemistry applications where structural diversity and complexity are crucial. This combination of generality, safety, and applicability to complex molecules represents a significant advancement in the functionalization of sulfoximines.

Benefits

• Enables efficient N-alkylation and N-arylation of sulfoximines under mild, visible-light conditions
• Uses safe, abundant, and stable starting materials such as aliphatic alcohols and aryl halides
• Compatible with a broad range of functional groups and complex pharmaceutical scaffolds
• Avoids hazardous reagents and explosive intermediates common in traditional methods
• Provides high yields and broad substrate scope including complex and heterocyclic molecules
• Employs transition metal (copper)-catalyzed radical capture and reductive elimination for C–N bond formation
• Offers configurationally stable sulfoximine products with valuable bioisosteric properties for drug design
• Utilizes photoredox catalysis enabling mild and sustainable reaction conditions

Applications

• Pharmaceutical lead optimization
• Drug metabolite synthesis
• Bioisostere library generation
• Late-stage drug modification
• Agrochemical development

Additional info

This methodology achieves N-alkylation and N-arylation of sulfoximines via transition metal-catalyzed radical capture. Visible-light photoredox catalysis generates alkyl radicals from NHC-alcohol adducts or aryl radicals from aryl halides. These radicals are intercepted by a copper-amido complex, forming a high-valent intermediate that undergoes reductive elimination. This approach enables the functionalization of complex pharmaceutical scaffolds under mild conditions, utilizing stable precursors like aliphatic alcohols and aryl halides.