Synthesis of N-Heterocycles and Their Reactive Precursors via Novel Pd/Cu-Catalyzed One-Pot Sequences (2011)

Heterocycles are found in a plethora of natural products and active ingredients and their preparation touches the very core of Organic Synthesis. Therefore, efficient syntheses of heterocycles are of paramount importance. The goal of this thesis was the development of novel one-pot reactions based on palladium- and/or copper-catalysis for the efficient synthesis of heterocycles or their precursors. Starting from simple building blocks and using simple catalyst systems, diverse functional molecules should be prepared by these methodologies. In the context of this work following goals were accomplished: 1) Development of a three-component synthesis of difficult-to-access 2,4-disubstituted pyrroles based on Sonogashira coupling. 2) Conception and methodological establishment of a pseudo four-component synthesis of 1,4-di(hetero)aryl substituted 1,3-diynes via sequential Sonogashira alkynylation-Glaser homocoupling. 3) Establishment of a decarbonylative alkynylation of heteroaromatic glyoxylyl chlorides as a new variation of Sonogashira coupling. On this basis a conceptually novel three-component synthesis of ynones, which are important building blocks in many heterocycle syntheses, was devised. 4) Conception and methodological establishment of a novel three-component synthesis of heterocyclic ynediones via catenation of glyoxylation and subsequent catalytic Stephens-Castro alkynylation in a one-pot fashion. Because the chemistry of ynediones is scarcely explored, the selective synthesis of 5-acyl pyrazoles was chosen to exemplify the synthetic potential of these reactive intermediates. 5) N-Heteroaromatic carboxylic acids and a-oxo carboxylic acids can be in situ activated with oxalyl chloride for Sonogashira or Stephens-Castro alkynylations and allow for the first time an efficient transformation of notoriously difficult N-heterocyclic substrates. 6) The sequentially Pd-catalyzed Masuda borylation–Suzuki coupling synthesis, which was established as a one-pot process, offers a direct and efficient strategy for the synthesis of 3-(hetero)aryl substituted (aza)indoles and 2,4-di(hetero)aryl substituted pyrroles. Besides the synthesis of 7-azaindole derivatives as analogs of variolin B this methodology was transposed to the preparation of symmetrical heterocycle-bridged bisindoles and to concise total syntheses of the marine alkaloids meridianin G, meridianin A, and hyrtinadine A. The obtained compounds were biologically evaluated in collaboration with Merck Serono, Darmstadt, on human cancer cell lines and on a broad panel of kinases, emphasizing that this methodology opens a rapid and efficient access to biologically active lead structures. 7) Conception and methodological establishment of a three-component Sonogashira coupling–azide-alkyne cycloaddition (Click reaction) sequence for the preparation of (aza)indolyl substituted triazoles. By this methodology a new lead structure for selective PDK1 inhibitors was found. All presented one-pot syntheses can be conducted under mild reaction conditions and are broad with respect to the substrate range. They are preparatively very simple, start from simple reactants and utilize simple catalyst systems. Moreover, the synthetic versatility of oxalyl chloride as a reagent in catalytic couplings for the introduction of the C1-carbonyl synthon (surrogate for carbon monoxide) is successfully demonstrated for the first time.