Decarboxylative functionalization: catalytic olefination and polyfluoroarylation of alkylcarboxylic acids

  • Decarboxylierende Funktionalisierung: Katalytische Olefinierung und Polyfluorarylierung von Alkylcarbonsäuren

Sun, Xiang; Ritter, Tobias (Thesis advisor); Bolm, Carsten (Thesis advisor)

Aachen : RWTH Aachen University (2021)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2021


Aliphatic carboxylic acids exist widely in nature and serve as an attractive feedstock in organic synthesis because of their availability and stability. Simple fatty acids have a large production in nature, and they are a potential alternative to fuel resources to produce hydrocarbons through decarboxylation. Due to the pre-installed functionalities and structural complexity of aliphatic carboxylic acids, late-stage decarboxylative functionalization can give rapid and straightforward access to various valuable derivatives that are helpful in drug discovery. Alkenes are among the most versatile building blocks and are widely used to produce polymers, detergents, and synthetic lubricants. Currently, alkenes are sourced from petroleum feedstocks such as naphtha. In light of the necessity to invent sustainable production methods, multiple approaches to producing alkenes from abundantly available fatty acids have been evaluated. However, all attempts have required at least one stoichiometric additive, which is an obstruction for applications at larger scales. To address this challenge, we report an approach to making olefins from carboxylic acids, in which every additional reaction constituent can be used as a catalyst. We show how abundant fatty acids can be converted to alpha-olefins and expand the method to include structurally complex carboxylic acids, giving access to synthetically versatile intermediates. Our approach is enabled by the cooperative interplay between a cobalt catalyst, which functions as a proton reduction catalyst, and a photoredox catalyst, which mediates oxidative decarboxylation; coupling both processes enables catalytic conversion of carboxylic acids to olefins. Polyfluoroarenes are useful building blocks in several areas such as drug discovery, materials, and crop protection. Polyfluoroaromatic synthesis can be approached by the defluorinative functionalization of readily accessible, simple fluoroarenes. Nucleophilic aromatic substitution (SNAr) of fluoride and transition-metal-catalyzed C–F bond functionalization represent two main routes. In these methods, preformed organometallic reagents such as alkyl- or aryl lithium, -Grignard, and –zinc reagents are generally required as carbon nucleophiles. However, each of these reagents comes with a common limitation in the substrate scope due to deleterious reactions. To address this problem, we show the first decarboxylative polyfluoroarylation of aliphatic carboxylic acids. The transformation is enabled by the radical addition of alkyl radicals to polyfluoroarenes via photoredox decarboxylation of readily available aliphatic carboxylic acids. The expedient synthesis results in a broad substrate scope and high functional group tolerance of the new carbon-carbon bond-forming reaction. In conclusion, we present a catalytic decarboxyolefination that may guide development towards a process for the sustainable synthesis of alpha-olefins from renewable carboxylic acids. The application on a laboratory scale, using both simple and complex carboxylic acids, can be implemented immediately and may serve for the late-stage modification of natural and unnatural products, as well as in drug discovery. In addition, we present a defluorinative alkylation with aliphatic carboxylic acids via photodecarboxylation. Polyfluoroaryl moieties can be easily introduced to molecules with structural complexity. The radical pathway of carbon radical addition to polyfluoroarenes coupled with photocatalysis can provide a platform for polyfluoroaromatics synthesis with other carbon radical precursors.