Small molecule fluorophores are critical components for modern microscopy studies. Classic xanthene fluorophores such as fluorescein, rhodol, and rhodamine have been widely used as fluorescence reporters due to their relatively high water solubility and cell permeability. However, the absorption and emission of the dyes falls within the visible region, limiting their utility in in vivo imaging. Recent studies have revealed that heteroatom substitution at the bridging positions of xanthenes (e.g. B, C, Si, Ge, N, P, S, Se, and Te) can dramatically red-shift absorption and emission wavelengths to far-red and near-infrared range. Unfortunately, synthesis of heteroatom xanthene fluorophores often involves several steps, including multiple lithium-halogen exchange reactions, leading to relatively low yields. Herein, we describe a solvent-free approach that can be used to successfully construct a universal template for heteroatom rhodamine and fluorescein analogs. Utilizing this approach, we synthesized NR612 (a phosphinate-based rhodamine 110 derivative), NR708 (a phosphinate ester-based tetramethyl rhodamine with bulky dimethoxy groups at the C-9 position), NR600 (a phosphinate-based Tokyo Green derivative), and RF560 (a borinate-based Tokyo Green derivative and H2O2 sensor), which are difficult or impossible to obtain using traditional routes. This methodology provides an expedient route to heteroatom xanthenes, enabling the further development of probes for in vivo imaging applications.

Solvent-free generation of universal templates for heteroatom xanthene fluorophores

ACS Spring 2022

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