Synthesis of substituted tetralins via electrochemical decarboxylative cycloalkylation
Enrico Lunghi 1 , a Pietro Ronco, a Federico Della Negra, b Beatrice Trucchi, b Massimo Verzini, b Daniele Merli, a Emanuele Casali, a C. Oliver Kappe, c,d David Cantillo, c,d *Giuseppe Zanoni a *
a University of Pavia, Italy, b Flamma S.p.A, Italy, c University of Graz, Austria, d Center for Continuous Flow Synthesis and Processing (CCFLOW), Austria
This work is focused on the electrochemical cyclization of tertiary carboxylic acids, forming new Csp 2 -Csp 3 bonds. A series of 9 parameters (support electrolyte, electrode material, substrate concentration, etc.) were optimized to increase yield and process conversion. The optimized conditions were then used for the cyclization of other substrates, including one of particular pharmaceutical interest. I took my idea from a literature background where Baran’s group succesfully decarboxilate tertiary carboxylic acids producing a radical that is immediately oxidized to carbocationic form that is trapped by a nucleophile, in that case an alcohol (2) . I substituted the nucleophile with an aromatic ring that could intramolecularly trap the carbocation produced from the tertiary carboxylic acid moiety, obtaining an intramolecular electrochemical decarboxylation-cyclization process. I started exploring this chemistry using a model substrate where R 1 = H and R 2 = CH 3, where the initial yield was about 15% and I optimized every parameter changing reaction conditions (70 reaction total) until the process reached a maximum of 72% yield. After the optimization I started to cyclize other substrates with different substituents, obtaining a small scope of the reaction, mainly to understand the compatibility of functional groups and the applicability of the chemistry I developed. I found that methoxy groups on aromatic ring are not compatible with my electrochemical process, due to low oxidation potential, while steric inderhed substituents on carboxylic acid lower the yield. I investigated then on the mechanism of the process. Since in literature is said that the process should follow a carbocationic pathway (2) , I decided to do first a radical scavenging experiment to exclude that the reaction follows a radical pathway, then, in another experiment, I tried to trap the possible carbocationic species with an alcohol that should act as nucleophile. References 1. Baran et al. Hindered Dialkyl Ether Synthesis with Electrogenerated Carbocations. Nature 2019, 573 (7774), 398–402. 2. Yamada et al. Electrochemical Synthesis of Substituted Morpholines via a Decarboxylative Intramolecular Etherification Org. Lett.2022, 24, 9, 1837–1841
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© The Author(s), 2023
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