Late-stage functionalization of arenes: from C-H amination to C-H oxygenation and deoxyfluorination

  • Late-Stage Funktionalisierung von Aromaten: Von C-H Aminierung zu C-H Oxidation und Deoxyfluorierung

Börgel, Jonas; Ritter, Tobias (Thesis advisor); Schoenebeck, Franziska (Thesis advisor)

Aachen (2019)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2019


Methods for late-stage aromatic C-N, C-O, and C-F bond formations are of imminent relevance in the field of drug discovery and development. The prevalence of aromatic C-N bonds in drug molecules demonstrates that diversification strategies at a late-stage are highly desired. Methods for C-O and C-F bond formations are especially of interest in the synthesis of potential metabolites and for metabolism block strategies, which are essential parts of the drug discovery process.Numerous reagents for C-H amination have been developed compared to the rather limited number for analogous reagents for C-H oxygenation and C-H fluorination. However, one-step C-H amination spanning a broad electronic scope of substrates had not been achieved. The use of the reagent [NH3-OMs]OTf in hexafluoroisopropanol (HFIP) overcomes previous substrate scope limitations and creates a method for diversification of lead structures at a late-stage. The unique hydrogen bonding properties of HFIP lower the lowest unoccupied molecular orbital (LUMO) of [NH3-OMs]OTf and enhance the reactivity of cationic reactive species such as ammoniumyl radicals in solution, which may lead to the observed higher reactivity. The idea of translating these effects to a mesyloxy-transfer reagent led to the development of a C-H oxygenation reaction employing bis(methanesulfonyl) peroxide. HFIP has also a reactivity boosting effect on bis(methanesulfonyl) peroxide with the difference of promoting electrophilic aromatic substitution, which is in contrast to the radical addition mechanism in the amination reaction with [NH3-OMs]OTf in HFIP. Very indicative for an electrophilic pathway is the formation of spectroscopically detectable charge transfer (CT) complexes between bis(methanesulfonyl) peroxide and arenes; analogous CT complexes have been previously identified as intermediates in electrophilic aromatic nitration and bromination reactions. The scope of the oxygenation reaction is further extended by employing Ru(bpy)3(PF6)2 as SET catalyst in acetonitrile to generate mesyloxyl radicals that add to electron poor (hetero)arenes. The resulting aryl mesylates bear the advantages of being stable phenol precursors, yet the mesyl group can be conveniently removed with the non-nucleophilic base LDA at low temperature or with fluoride anions. The latter discovery led to a new deoxyfluorination method with PhenoFluorMix that provides the corresponding aryl fluorides from the aryl mesylates directly. Moreover, aryl mesylates can be employed as substrates in the deoxyfluorination with fluorine-18 with the potential for radiolabeling of complex small molecules.