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- Challenges in C(sp3)–C(sp3) Bond Construction:
- Classical methods involve organometallic reagents or strong bases.
- Transition metal-catalyzed cross-coupling reactions have been a focus.
- Rise of Radical Chemistry:
- Recent decade saw growth in radical chemistry via mild methods, often involving transition metals or photocatalysts.
- New Strategy for C(sp3)–C(sp3) Bond Formation:
- A novel approach uses photoexcited 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) and alkyl sulfones.
- Hantzsch esters (HEs) act as potent reductants for photoredox catalysis.
- Key Development:
- Excited-state alkyl-DHPs, without external photocatalysts, facilitate single-electron transfer.
- Electron-deficient alkyl sulfones explored as less-explored precursors for radical cross-coupling (RCC) reactions.
- Experimental Validation:
- Model substrate experiments demonstrate successful C(sp3)–C(sp3) bond formation under optimized conditions.
- Reaction scope expands to various radical precursors, including primary radicals.
- Mechanistic Insights:
- Mechanistic studies reveal the importance of excited-state interactions and electron transfer.
- Proposed mechanism involves a light-triggered reduction of alkyl-DHPs and subsequent radical cross-coupling.
- Synthetic Potential:
- Demonstrates the synthesis of diverse compounds, including modifications of medicinally relevant molecules.
In a breakthrough for synthetic organic chemistry, researchers have unveiled a metal-free strategy for constructing C(sp3)–C(sp3) bonds, a key element in creating complex natural products, pharmaceuticals, and functional materials. Traditionally, achieving this bond involved challenging methods with organometallic reagents or strong bases. However, recent developments in radical chemistry, particularly using mild methods with transition metals or photocatalysts, have sparked interest.
The new strategy, outlined in a recent paper, revolves around leveraging the unique properties of photoexcited 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) and alkyl sulfones. Notably, the researchers managed to bypass the need for transition metals or photocatalysts in their approach.
The key to their success lies in the use of excited-state alkyl-DHPs, acting as potent reductants in the absence of external photocatalysts. These compounds facilitate single-electron transfer, leading to the formation of open-shell radical species crucial for C(sp3)–C(sp3) bond construction. Additionally, electron-deficient alkyl sulfones, a less-explored precursor, were found to be promising for radical cross-coupling reactions.
Experimental validation of the proposed strategy involved model substrate experiments, demonstrating a high yield of the desired cross-coupled product. The reaction scope was further expanded to various radical precursors, including primary radicals, showcasing the versatility of the method.
Mechanistic insights revealed the importance of excited-state interactions and electron transfer in the process. The proposed mechanism involves a light-triggered reduction of alkyl-DHPs and subsequent radical cross-coupling, offering a metal-free alternative to traditional methods.
The researchers also demonstrated the synthetic potential of their methodology by successfully modifying medicinally relevant molecules. This innovative approach not only streamlines the construction of C(sp3)–C(sp3) bonds but also opens up new possibilities for diverse chemical synthesis without the need for transition metals or photocatalysts.
C(sp3)–C(sp3) Radical-Cross-Coupling Reaction via Photoexcitation
- Sandeep Patel, Arijit Chakraborty, and Indranil Chatterjee*
- Metal-Free Bond Formation
- Radical Chemistry Advancements
- Innovative Synthetic Approach
- Avoiding Transition Metals
- Stable Precursors, High Yield
- Radical Cross-Coupling (RCC): A novel strategy for C(sp3)–C(sp3) bond formation without transition metal or photocatalyst, using excited-state 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) and redox-active sulfones.
- Reaction Optimization: The reaction conditions involve UV light (365 nm), sodium acetate additive, and ethanol at 45 °C under a nitrogen atmosphere.
- Scope: Successful RCC demonstrated across a range of radical precursors, including secondary, tertiary, and even challenging primary radicals.
- Control Experiments: Mechanistic studies involve radical scavenger experiments, UV–visible spectra analysis, fluorescence quenching, and NMR studies.
- Light Dependence: The reaction is light-dependent, supported by light ON/OFF experiments and cyclic voltammetry.
- Synthetic Potential: Application of RCC to modify medicinally relevant molecules, showcasing its synthetic versatility.
- Data Availability: The study provides data availability information, including primary NMR files and supporting information.
Summary
- The strategy avoids the need for transition metals or photocatalysts in C(sp3)–C(sp3) bond formation.
- Excited-state 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) act as electron donors, and redox-active sulfones act as electron acceptors.
- Reaction optimization involves UV light, sodium acetate, and ethanol under specific conditions.
- The RCC is successful with various radical precursors, demonstrating broad scope.
- Control experiments support the proposed mechanism, emphasizing the role of light and electron transfer.
- The study highlights the synthetic potential by modifying complex molecules under mild conditions.
- Data availability for the study is provided in the published article and its supporting information.