Abstract
With the development of C–H activation reaction in recent several decades, late-stage functionalization has been of interest as an efficient strategy to accelerate the diversification of highly valuable molecules in drug discovery and related fields. It can give rapid and straightforward access to the target molecules without multistep de novo synthesis. The study of aromatic C–H functionalization has a vast history, but there are two major challenges remaining to achieve broadly useful aromatic reactions, which can be utilized in late-stage
functionalization from arene C–H bonds: reactivity and selectivity. To address these two challenges, we describe the strategy to achieve site-selective C–H oxygenation and
fluorination from arene C–H bonds in two steps via aryl sulfonium intermediates in this thesis.
Due to the importance of aromatic C–O and C–F bonds in chemical synthesis and drug
discovery, site-selective late-stage oxygenation and fluorination are attractive. Several methods about direct late-stage C–H oxygenation and fluorination have been developed with the novel reagents and transition metal catalysts so far. However, the positional selectivity was problematic. In other words, no other one- or two-step procedures are currently available to
install functionality into complex arenes with high site-selectivity. To overcome the
limitations, we used the strategy of a site-selective C–H functionalization of arenes by
thianthrenation to generate a synthetic lynchpin, which can be participated in the diverse transformation. Based on the higher reduction potential of arylthianthrenium salts when comparing to aryl halides, single electron reduction of the thianthrenium moiety is possible at a potential that Cu(III) is feasible, from which facile reductive elimination could occur. So the
metallophotoredox catalysis can be conceptually possible in the formation of aromatic C–O and C–F bonds via arylthianthrenium salts, especially at a late stage.
We disclose the first site-selective late-stage aromatic C–O bond formation to synthesize
phenols and aryl ethers from arene C–H bonds in two steps via arylthianthrenium
intermediates. A variety of different oxygen nucleophiles, including water, phenols, primary, and secondary alcohols, can be coupled with simple arenes as well as complex drug-like small molecules at a late stage. Inspired by the success of C–H oxygenation, we also had an investigation on the C–H fluorination via arylthianthrenium salts. Nucleophilic fluorination source was discovered as a suitable coupling partner. The use of a stoichiometric amount of inexpensive Cu(I) salts and acetone as solvent also had a major effect on the suppression of
the hydrodefunctionalization products, which are difficult to separate from the desired product by columns. Both of these overall transformations can construct aromatic C–O and C–F bonds with high and predictable site selectivity and feature broad functional group tolerance, especially protic groups, such as alcohols, halides and pseudohalides, which are incompatible with transition metal-catalyzed reactions. The sequence differs conceptually from all previous
arene oxygenation, and fluorination reactions in that functionality can be incorporated into complex small molecules at a late stage site-selectively, which has not been shown via aryl halides.
Herein, we fill the gap of late-stage site-selective C–O and C–F bond formation from arene C–H bonds. We anticipate that our C–O and C–F bond formation reactions will be a valuable addition to the set of aromatic late-stage C–H functionalization reactions with imminent relevance to drug discovery and development.
