Catalyst- and Additive-free, Regioselective 1,6-Hydroarylation of para-Quinone Methides with Anilines in HFIP

A simple and efficient method for the synthesis of diarylmethyl-functionalized anilines through the hexafluoroisopropanol (HFIP)-mediated regioselective 1,6-hydroarylation reaction of para-quinone methides (p-QMs) with anilines under catalyst- and additive-free conditions is reported. Various kinds of p-QMs and amines (e. g. primary, secondary and tertiary amines) are well tolerated in this transformation without the pre-protection of amino group, and the corresponding products could be generated with good to excellent yields and satisfactory regioselectivity under the optimized reaction conditions. In addition to adaptable amine compounds, indoles and their derivatives are also compatible with this reaction system. This transformation can be easily extended to a gram scale-synthesis level to synthesize the target product. Furthermore, it is worth noting that some complex small aniline molecules with biological activity can be selectively modified using this method. The possible reaction mechanism is proposed through the step-by-step control experiments and DFT calculations, showing that the key process for achieving the regioselective 1,6-hydroarylation of p-QMs is the hydrogen bonding effect of HFIP to substrates.

Automated summary

This research reports a simple and efficient method for the synthesis of diarylmethyl-functionalized anilines. The reaction utilizes hexafluoroisopropanol (HFIP) as a mediator and occurs under catalyst- and additive-free conditions. Various types of para-quinone methides (p-QMs) and amines are well tolerated in this transformation, producing the desired products with good to excellent yields and satisfactory regioselectivity. Additionally, this method can also be applied to indoles and their derivatives, and is scalable to gram-scale synthesis. It is worth noting that this method can selectively modify complex small aniline molecules with biological activity.