Divergent synthesis of 5',7'-difluorinated dihydroxanthene-hemicyanine fused near-infrared fluorophores.

We describe an expedient access to a 5',6',7'-trifluoro dihydroxanthene-hemicyanine fused scaffold in 2 steps and 54% overall yield from the corresponding salicylic aldehyde. A 6'-regioselective nucleophilic aromatic substitution (SNAr) reaction with a wide range of nitrogen, sulfur or selenium nucleophiles then gives access to 16 near-infrared (NIR) fluorophores emitting in the 710-750 nm range. We also report the experimental and theoretical photophysical investigations of these unique optical agents that include the first series of 6'-heavy atom substituted dihydroxanthenes, extending the pool of polyfluorinated markers for biomedical and material applications.

Synthesis of N,N-Dialkylamino-nor-Dihydroxanthene-Hemicyanine Fused Near-Infrared Fluorophores and Their First Water-Soluble and/or Bioconjugatable Analogues.

The effective synthesis of extended conjugated N,N-dialkylamino-nor-dihydroxanthene-based fluorophores is described from diversely functionalized salicylic aldehydes. The access to these original fluorescent derivatives proceeded in two steps through a one-pot construction of the unusual nor-dihydroxanthene (nor-DHX) scaffold followed by a diversification step providing a wide variety of nor-DHX-hemicyanine fused dyes emitting in the range of 730-790 nm. The versatility of our approach has enabled a further extension to the late-stage introduction of negatively/positively charged polar groups onto their terminal nitrogen heterocyclic subunit, thereby giving access to the first water-soluble and/or bioconjugatable members of this emerging class of NIR fluorophores.

Divergent Synthesis of Dihydroxanthene-Hemicyanine Fused Near-Infrared Fluorophores through the Late-Stage Amination of a Bifunctional Precursor.

A late-stage amination of a bifunctional dihydroxanthene (DHX) scaffold is reported to access a wide variety of new near-infrared (NIR) chromophores/fluorophores. The divergent approach allows the coupling of aliphatic and aromatic amines and readily provides molecular diversity shedding light on the structure-fluorescence relationship of this emerging class of NIR fluorophores.