A New Photoredox-Catalyzed Intermolecular Cyclopropanation Reaction

Significance 

Cyclopropanes are valuable intermediates in organic synthesis because of their inherent ring strain and reactivity, which make them essential components in biologically active molecules, including several important pharmaceutical products such as nirmatrelvir (Paxlovid), montelukast (Singulair), and abacavir (Ziagen). However, the cyclopropanes synthesis remains a challenge because their high strain energy predisposes them to ring-opening reactions. A common method to synthesize cyclopropanes involves metal-catalyzed cyclopropanation, where an alkene reacts with a diazoalkane or another carbene precursor. While effective, this method requires stringent safety protocols because of the high reactivity and toxicity of diazo compounds. Therefore, there is an urgent need to develop safer, more efficient alternative procedures. To this end, new study published in the prestigious Journal Science, and conducted by Dr. Dhruba Poudel, Amrit Pokhrel, Dr. Raj Kumar Tak, Dr. Majji Shankar, and led by Professor Ramesh Giri from the Department of Chemistry at The Pennsylvania State University developed the photoredox-catalyzed intermolecular cyclopropanation method. This new safer and innovative approach uses simple active methylene compounds and unactivated alkenes, effectively does not diazoalkanes.

The research team selected 4-phenylbutene as the alkene and diethyl malonate as the active methylene compound for their experiments and used 4CzIPN (a complex organic molecule as the photocatalyst and excited with a 440 nm blue LED light. They also used N,N-dimethylformamide (DMF), and cyclohexyl iodide (cHex-I) solvents as a secondary catalyst to help the reaction proceed. Moreover, the authors tested various oxidizing agents including di-tert-butyl peroxide, hydrogen peroxide, and pyridinium N-oxide but these agents didn’t produce cyclopropanes. However, when they combined peroxide oxidants with alkyl iodides, especially cHex-I, they successfully produced cyclopropanes in significant amounts. They found that using both O₂ and cHex-I was crucial for getting high yields, achieving up to 99% of the desired product. Without O₂ or alkyl iodide, no cyclopropanes were formed, highlighting the importance of these components. They also discovered that replacing cHex-I with molecular iodine (I₂) could yield similar high results.

The researchers tested different solvents, including acetonitrile, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), and toluene, and found that DMF gave the best results. They also screened various photocatalysts, finding that 4CzIPN was the most effective with a 99% yield. Other photocatalysts like Eosin Y sodium salt, [Ir(dFCF₃ppy)₂(bpy)]PF₆, and [Ir(ppy)₃] also showed good results but were less effective than 4CzIPN. The researchers reported the optimal conditions for the reaction to be 0.1 mol% of 4CzIPN as the photocatalyst, a 440 nm blue LED light source, DMF as the solvent, dioxygen (O₂ from a balloon or air) as the oxygen source, and either cHex-I or I₂ as the iodine co-catalyst.

The researchers confirmed the formation of I₂ in the reaction mixture using UV-Vis and fluorescence spectroscopy. I₂ acted as an electron donor, reducing the photocatalyst radical cation and allowing the catalytic cycle to continue. When the reactions were conducted under a nitrogen atmosphere or without alkyl iodide, no cyclopropanes were formed, which emphasized the essential role of superoxide ions (O₂•⁻) in the process. Experiments with long-chain alkyl iodides (like dodecyl iodide and hexadecyl iodide) resulted in alkyl formates, indicating that alkyl radicals react with O₂ to form peroxy radicals. To confirm that the reaction was driven by light, they performed an on-off light experiment. Cyclopropane products formed only when the blue LED light was on, which confirms the involvement of a photoredox mechanism. They also isolated dimerized products, which verified the formation of α-carbon radicals from the active methylene compounds. Moreover, they when reactions was performed with α-iodomalonates, it did not produce cyclopropanes, which make the rule out these compounds as intermediates in the reaction. It is noteworthy to mention the team studied several active methylene compounds and alkenes to demonstrate the broad applicability of their cyclopropanation method and found that diesters like diethyl malonate and dimethyl malonate had impressive yields above 90%, ketone esters such as ethyl acetoacetate had an 87% yield, and sulfonyl compounds like methylsulfonylmethane achieved 88% yield. Carbonylated heterocycles, including furanyl, thiophenyl, and pyridyl rings with esters, showed as well good yields between 75-85%. Cyclopropyl isocyanate, which represents isocyanates and amides, had an 84% yield. Moreover, for alkenes, terminal alkenes, whether linear or cyclic, produced yields over 90%, while internal disubstituted alkenes had yields between 80-85%. More complex molecules such as estrone, dihydrocholesterol, and indomethacin had yields ranging from 70-90%. The reaction also worked well with complex pharmaceuticals like ketorolac and penicillin G, which highlight the compatibility with a wide range of substances. Overall, this reaction exhibited broad compatibility with various active methylene compounds and alkenes, tolerating functional groups like esters, nitriles, sulfonyls, and carbonylated heterocycles. It was also effective with complex pharmaceuticals and natural products, producing cyclopropanated products without significant byproducts.

In conclusion, the new innovative procedure by Professor Ramesh Giri and his team is a significant advancement in medicinal chemistry and have successfully developed a safer, greener, and broadly applicable alternative for synthesizing cyclopropanes via photoredox-catalyzed intermolecular cyclopropanation. The new approach expected to have broad applications particularly in synthesizing cyclopropyl-containing drugs, opening new avenues for drug design and discovery.

Reference

Poudel DP, Pokhrel A, Tak RK, Shankar M, Giri R. Photosensitized O2 enables intermolecular alkene cyclopropanation by active methylene compounds. Science. 2023;381(6657):545-553. doi: 10.1126/science.adg3209.

Go to Science.

Check Also

Development of a Solid Polymer Electrolyte for High-Performance Aluminum Batteries: Enhancing Electrochemical Stability and Ionic Conductivity with PEO and Fumed Silica - Advances in Engineering

Development of a Solid Polymer Electrolyte for High-Performance Aluminum Batteries: Enhancing Electrochemical Stability and Ionic Conductivity with PEO and Fumed Silica