A Redox-Neutral Copper Metallaphotoredox Trifluoromethylation of Aryl Bromides via Reductively-Activated N-siloxyphthalimide Reagents

Abstract

The trifluoromethylation of aryl halides is a particularly desirable transformation in medicinal chemistry due to the prevalent incorporation of the trifluoromethyl moiety in pharmaceuticals. However, previous methodologies have utilized costly trifluoromethylating reagents or proposed net-oxidative pathways with a sacrificial stoichiometric oxidant. Herein, copper metallaphotoredox catalysis was combined with reductively-activated N-siloxyphthalimide reagents to achieve a redox-neutral aryl bromide trifluoromethylation using readily-available Ruppert-Prakash reagents. The selectivity and efficiency of this reaction was enhanced through mechanistically-guided, hypothesis-driven optimization. A small-scale scope was also evaluated to show the generality of the reaction. While optimization studies afforded modest yields, high conversion rates from starting material indicate efficient transformation. Future strategies to enhance reaction conversion are prompted by a hypothesis of premature organosilane reagent degradation. This exploration of redox-neutral metallaphotoredox trifluoromethylation offers an efficient pathway for synthesizing valuable compounds, with implications for expedited trifluoromethylated small molecule synthesis.