Synthesis of Ketones by Utilizing Thioesters as "Radical Weinreb Amides"

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2021-08-03

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Abstract

Radical-mediated ketone synthesis has been tested via intermolecular and intramolecular reactions. Photoredox catalysis and classical means of radical generation were tested to generate radicals. N-Boc-L-proline and N-phenyl pyrrolidine were reacted with electrophilic thioesters such as S-(tert-butyl) benzothioate, S-adamantane benzothioate, S-phenyl benzothioate, S-(4-fluoro)phenyl benzothioate and S-(pentafluoro)phenyl benzothioate. Different solvents including DMF, DMSO, MeCN, CH2Cl2, THF, PhMe were used as solvents, and reactions were set at 23oC and 45oC. LC-MS analysis revealed that N-Boc-pyrrolidine has been generated in the reaction mixture, which proves that we were making radicals, while thioesters such as S-pyridyl benzothioate, S-(tert-butyl) benzothioate, and S-adamantane benzothioate are unstable in the presence of photocatalyst. The presence of a thiol peak in LC-MS is a sign of thioester hydrolysis by the iridium photocatalyst. Additionally, there is a peak that has the m/z of disulfide. This means that in the catalytic cycle of iridium photocatalyst, Ir lll is able to oxidize the thiol into thiyl radical. Then, dimerization happens which ends up in disulfide formation through a new S–S bond formation. Since Aryl radicals are more nucleophilic radicals, they should be less endothermic to make oxygen-centered radicals. We investigated coupling between iodotoluene as an aryl radical source with thioesters using CzIPN as the photocatalyst and K2HPO4 as the base. LC-MS analysis revealed that the above-mentioned thioesters are also unstable in the presence of CzIPN. We investigated intramolecular reactions for synthesizing cyclic ketones. The malonated substrate was synthesized in 50% yield before our research came to an end.

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Ketones ǂx Synthesis, Thiols, Free radicals (Chemistry), Amides

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