Intramolecular C–H insertion to form dihydrobenzofurans via continuous flow photolysis of aryldiazoacetates Katie S. O’Callaghan 1 , Stuart G. Collins 1 , Anita R. Maguire 1,2 1 Synthesis and Solid State Pharmaceutical Centre, University College Cork, Ireland 2 School of Pharmacy, University College Cork, Ireland Recent advances in continuous flow technology have led to a renewed focus on the potential of photolysis. 1-4 This work demonstrates the powerful combination of photochemistry and flow chemistry, which offers many advantages, including the ability to safely generate and use α-diazocarbonyl compounds in synthesis. 5-7 Our group has recently described the enantioselective rhodium mediated C–H insertion of aryldiazoacetates 1 – 3 leading selectively to the trans or cis dihydrobenzofurans 4 – 6 as the major product, depending on the catalyst employed. 8 We wished to explore if this transformation could be effected photochemically, providing the dihydrobenzofuran moiety in a metal-free transformation. Efficient C–H insertion was achieved under photochemical conditions in the absence of a metal using continuous flow technology for a range of aryldiazoacetates 1 – 3 , using either a medium pressure mercury lamp (250–390 nm) or LEDs (365 nm) with comparable synthetic outcomes. Significantly, addition of 4,4’-dimethoxybenzophenone, a triplet photosensitiser, results in improved efficiency of the intramolecular C–H insertion with complete consumption of aryldiazoacetates 1 – 3 within 3 minutes of photolysis, whereas 10 minutes of irradiation is required in the absence of the photosensitiser. The diastereomeric ratio of the dihydrobenzofuran products was notably altered in the photosensitised reactions (2.7:1.0 cf. 1.0:1.0 in the absence of the photosensitiser) leading to preferential isolation of the trans dihydrobenzofurans 4a – 6a (up to 50% yield), while the cis and trans diastereomers of 4 – 6 are recovered in essentially equimolar amounts in the absence of a photosensitiser (up to 26% yield), ( Scheme 1 ).
Scheme 1. Photochemical intramolecular C–H insertion of aryldiazoacetates using continuous flow technology. Overall, we have demonstrated a metal-free C–H insertion via flow photolysis of aryldiazoacetates 1 – 3 with increased reaction efficiency in the presence of 4,4’-dimethoxybenzophenone. Effecting C–H insertion in the absence of a metal catalyst is notable from a green chemistry perspective. References 1. Politano, F.; Oksdath-Mansilla, G. Org. Process Res. Dev. 2018 , 22 (9), 1045–1062. 2. Donnelly, K.; Baumann, M. J. Flow. Chem. 2021 , 11 , 223–241. 3. Buglioni, L.; Raymenants, F.; Slattery, A.; Zondag, S. D. A.; Noël. Chem. Rev. 2022 , 122 (2), 2752–2906. 4. Rehm, T. H. Chem. Eur. J. 2020 , 26 (71), 16952–16974. 5. Deadman, B. J.; Collins, S. G.; Maguire, A. R. Chem. Eur. J. 2015 , 21 (6), 2298–2308. 6. Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. Chem. Soc. Rev. 2016 , 45 (18), 4892–4928. 7. O’Mahony, R. M.; Lynch, D.; O’Callaghan, K. S.; Collins, S.G.; Maguire, A. R. Org . Process Res . Dev . 2021 , 25 (12), 2772–2785. 8. Buckley, A. M.; Crowley, D. C.; Brouder, T. A.; Ford, A.; Rao Khandavilli, U. B.; Lawrence, S. E.; Maguire, A. R. ChemCatChem 2021 , 13 (20), 4318–4324.
P50
© The Author(s), 2023
Made with FlippingBook Learn more on our blog