Decarboxylative C(sp3 )−O Cross-Coupling

Alkyl aryl ethers are an important class of compounds in medicinal and agricultural chemistry. Catalytic C(sp3)−O cross‐coupling of alkyl electrophiles with phenols is an unexplored disconnection strategy to the synthesis of alkyl aryl ethers, with the potential to overcome some of the major limitations of existing methods such as C(sp2)−O cross‐coupling and SN2 reactions. Reported here is a tandem photoredox and copper catalysis to achieve decarboxylative C(sp3)−O coupling of alkyl N‐hydroxyphthalimide (NHPI) esters with phenols under mild reaction conditions. This method was used to synthesize a diverse set of alkyl aryl ethers using readily available alkyl carboxylic acids, including many natural products and drug molecules. Complementarity in scope and functional‐group tolerance to existing methods was demonstrated.

Cross-Coupling of Alkyl Redox-Active Esters with Benzophenone Imines: Tandem Photoredox and Copper Catalysis

Jonathan Balon, Xile Hu, Runze Mao

Alkyl amines are an important class of organic compounds in medicinal and materials chemistry. Until now very have been very few methods for the synthesis of alkyl amines by metal‐catalyzed cross‐coupling of alkyl electrophiles with nitrogen nucleophiles. Described here is an approach to employ tandem photoredox and copper catalysis to enable the cross‐coupling of alkyl N‐hydroxyphthalimide esters, readily derived from alkyl carboxylic acids, with benzophenone‐derived imines. Hydrolysis of the coupling products furnish alkylated primary amines. Primary, secondary, and tertiary alkyl groups can be transferred, and the coupling tolerates a diverse set of functional groups. The method allows rapid functionalization of natural products and drugs, and can be used to expedite syntheses of pharmaceuticals from readily available chemical feedstocks.

2018

Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis

Jonathan Balon, Adrian Frey, Xile Hu, Runze Mao

Amines are a quintessential moiety in bioactive molecules, pharmaceuticals and organic materials. Transition-metal-catalysed C–N coupling of aryl electrophiles has been established as a powerful and reliable method for amine synthesis. However, the analogous C–N coupling of alkyl electrophiles is largely under-developed due to the decomposition of metal alkyl intermediates by β-hydrogen elimination and difficulty in C(sp3)–N reductive elimination. Here, we provide a general strategy for amination of alkyl electrophiles by merging photoredox and copper catalysis. Photoredox catalysis allows the use of alkyl redox-active esters, recently established as a superior class of alkyl electrophiles, whereas copper catalysis enables C(sp3)–N cross-coupling. Decarboxylative amination can be used for the synthesis of a diverse set of alkyl anilines with high chemoselectivity and functional-group compatibility. Rapid functionalization of amino acids, natural products and drugs is demonstrated.

2018

Aliphatic Carboxylic Acids as Coupling Partners in Carbon-Heteroatom Bond-Forming Reactions

Runze Mao

Carboxylic acids are one of the most suitable starting materials for synthesis. They are readily available and therefore inexpensive, stable and non-toxic. Many carboxylic acids can be obtained directly from natural resources, thus avoiding the extraction of fossil resources, such as oil or natural gas, in the production of chemicals. Furthermore, renewable carboxylic acids derived from biomass have a wide structural diversity (e.g., amino acids, fatty acids and sugar acids), which not only holds greater potential for the synthesis of complex molecules, but also advances the development of green chemistry. In this context, this thesis aims at establishing new carbon-heteroatom coupling reactions with carboxylic acids as versatile coupling partners. These reactions are hitherto unknown, which not only fill some of the gaps in synthetic organic chemistry, but also provide solutions for the rapid assembly of bioactive molecules. In order to overcome the challenge of forming C(sp3)-heteroatom bonds, Chapters 4, 5 and 6 detail the development of photoredox/copper bi-catalytic systems and their applications in decarboxylative C(sp3)-N and C(sp3)-O coupling reactions. These methods are not only compatible with numerous functional groups, but also allow for rapid late-stage functionalization. More importantly, these methods can simplify the pathway for building drug core skeletons, highlighting the potential of these methods to expedite drug discovery. To bridge the disconnection in the synthesis of trifluoromethylthioesters from carboxylic acids, Chapter 7 describes the establishment of a "umpolung" strategy and its application in the conversion of carboxylic acids to trifluoromethylthioesters. This approach provides the most concise synthetic pathway to date for the synthesis of trifluoromethylthioesters, which not only accommodates a variety of functional groups, but also allows for the rapid functionalization of carboxylic acid-containing natural products and drug molecules. In summary, this thesis illustrates how novel catalytic methods can be used to convert inexpensive, readily available and environmentally benign aliphatic carboxylic acids into high value-added compounds.

EPFL2020

Aliphatic Carboxylic Acids as Coupling Partners in Carbon-Heteroatom Bond-Forming Reactions

Runze Mao

EPFL2020