Abstract:
Ketones constitute an important structural motif in organic chemistry and the search for new methods to synthesize them is still in high demand. Thioesters as derivatives of carboxylic acids serve as fundamental building blocks in biochemistry and represent a highly attractive acyl source. Selective activation of the relatively weak C(O)–S bond can be achieved by cross couplings, which are a valuable option to traditional synthetic methods. Advantageously, functionalized substrates as well as low cost and environmentally friendly reagents can be used with high atom economy under mild reaction conditions. While palladium dominates in the choice of metal catalyst for such transformations, the replacement of this precious metal by nickel is incentivized by its favorable cost efficiency, abundance and versatile chemical properties, which are presented in chapter 1. Both aspects, thioesters as acyl sources and nickel catalysis, were combined in this thesis with the overall aim of developing new approaches for ketone syntheses.
Chapter 3 was targeted on ketone synthesis by the so called Liebeskind–Srogl coupling, in which thioesters and organoboron compounds react under palladium catalysis and stoichiometric amounts of a copper(I) reagent. To date, Liebeskind–Srogl couplings are limited to palladium catalysis, wherefore preliminary studies on a nickel catalyzed Liebeskind–Srogl coupling were performed. It was found that the cross coupling of aryl thioesters and organoboroxines enables the formation of benzophenone, although the mediator of the reaction is not nickel but solely copper(I).
In chapter 4, the focus shifted from traditional cross couplings to cross electrophile couplings. Benzylic alcohols were coupled with thioesters under Lewis acids assistance and nickel catalysis, yielding ketones instead of the expected transesterification products. The reaction depends strongly on the substituents of the two substrates. Thioesters with different acyl moieties can be used to give the desired ketones, while the formation of thioether byproduct is minimized with an electron withdrawing substituent on the thiol moiety. Contrariwise, electron rich benzylic alcohols with a methoxy substituent in para position are required for ketone formation, but benzylic chlorides are also suitable substrates, being more tolerant to changes in substituents. Mechanistically, a classical cross coupling mechanism was excluded. Instead, the alcohol is converted in situ to benzyl chloride by TMSCl, leading to a more facile formation of a benzyl radical. The latter seems to be involved in a radical chain mechanism as the main catalytic cycle. Thioesters are presumably activated by interaction with Lewis acid Cp2TiCl2, producing acyl radicals as the active intermediate.
Cross-Electrophile Coupling