New Reagents for Organofluorine Compounds Synthesis
Fluorine incorporation is important for the design of new drugs and materials, because it can often improve the chemical, physical and biological properties of organic molecules. But nature is not good at making organofluorine compounds. People need to develop fluorination agents and methods.
Fluoroalkylsilicon reagents, such as TMSCF3 (Rupert-Prakash reagent), TMSCF2H and others are widely used reagents in the synthesis of organofluorine compounds. Among various fluorine-containing molecules, the secondary fluoroalkyl alcohols are of particular importance; monoamine oxidase A inhibitor Befloxatone and antitumor agent Z are examples of bioactive molecules containing trifluoroethanol motif (Fig. 1a). Anionic activation of C-Si bond of fluoroalkylsilicon reagents by Lewis bases is a powerful method to transfer α-fluoro carbanions into aldehydes, affording fluoroalkyl alcohol products (Fig. 1b). However, the synthetic chemistry based on carbonyl group (Fig. 1b) possesses some limitations: 1) many aldehydes are not stable and/or need multistep synthesis; 2) it is hard to control the regioselectivity when there are more than one aldehyde sites in the same molecule. Moreover, the design and synthesis of pharmacuticals call for strategies to incorporate important structural motifs at late-stage, because this will aviod de novo synthesis. Therefore, we enviosioned that the development of organosilicon reagents such as 1a and 2a which allows direct transfer of trifluoroethanol and difluoroethanol into organic molecules would represent a conceptually different means to construct fluoroalkyl alcohols (Fig. 1c).
Reagent 1a and 2a are easily prepared in three steps from commercial available starting materials. However, when we test the anionic activation mode (the most widely used strategy) to activate the C-Si bond of 1a, no desired product was observed, but the reagent was consumed completedly (Fig 2a). We think that the decomposition of compound 1a might result from the facile fluoride elimination of β-fluoro carbanions (Fig. 2b). It is known that fluorine radical possesses much higher energy than fluorine anion does. Therefore, we envisioned that in-situ generated carbon radical from alkoxyl radicals should not prefer β-F elimination. Consequently, they could be trapped by radical acceptors to generate trifluoroethanol transfer products (Fig. 2b).
Based on the the idea of radical activation of C-Si bond, we developed an efficient methodology to direct transfer of tri- and di-fluoroethanol units into molecules. Various reactions such as allylation, alkylation and alkenylation reactions have been achived enabling efficient synthesis of tri(di)fluoromethyl group substituted alcohols. The broad applicability and general utility of the approach are highlighted by late-stage introduction of these fluoroalkyl groups to complex molecules and the synthesis of antitumor agent Z and its difluoromethyl analog Z'.
If you are interested in the radical activation of organosilicon reagents and fluorination reactions, check out our article at "Direct transfer of tri- and di-fluoroethanol units enabled by radical activation of organosilicon reagents" in Nature Communications (https://www.nature.com/article...).