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Small-molecule fluorophores are compounds that absorb and re-emit light that see many applications in areas including biological imaging, environmental testing, and laser dyes. Yet despite the wide range of fluorophores currently used in these applications, synthetic barriers limit the amount of fluorophores that we can make and utilize for these purposes. Rational synthetic modification of these compounds provides new chemical tools with improved photophysical properties, sensitive and selective luminescent responses, and spatiotemporal imaging capabilities. Many commercially available or readily accessed small-molecule fluorophores incorporate a hydroxyl moiety as a donor component of the chromophore. Amino analogues of these compounds exhibit favorable photophysical properties, pH sensitivity, and synthetic tenability, but are often not commercially available and are extremely difficult to synthesize. Current methods for the conversion of hydroxyfluorophores to aminofluorophores primarily utilize Buchwald–Hartwig coupling as the key synthetic step, which is undesirable due to its intolerance of pendant functional groups, high cost, and the high temperatures and metallic catalysts required. An operationally simple and robust method for the conversion of hydroxyfluorophores to aminofluorophores is described herein using the Smiles Rearrangement as the key synthetic step. Contrary to the traditional Smiles Rearrangement pathway, our method utilizes an amide-based alkyl linker, which subsequently hydrolyzes to yield the primary amine. Additionally, this method is especially advantageous as it presents the possibility of a future one-pot process. Investigation of various nitrogen-containing linkers revealed the base-promoted rearrangement of amides can provide the desired products under exceptionally mild conditions. Future fine tuning of this method could provide facile access to previously inaccessible aminofluorophores that complements current multi-step, metal-catalyzed processes.
Elghawy, Omar, "Facile Conversion of Hydroxyfluorophores to Aminofluorophores via Smiles Rearrangement" (2019). Chemistry Honors Papers. 9.
This research was supported by an NSF (MRI 1726836) grant for funding of a 300 MHz NMR spectrometer.