Divergent Synthesis Of 5’,7’-Difluorinated Dihydroxanthene-Hemicyanine Fused Near-Infrared Fluorophores

Replacement of C-H bonds by C-F bonds is a useful tool to discover small molecules and organic materials with unique properties.Till now,around 25%pharmaceuticals and agrichemicals in the market are fluorinated compounds,such as anticancer drug Gefitinib,HIV-I inhibitor Emtricitabine.Fluorinated materials are also approved to have unique properties compared with their non-fluorinated analogs,such as polytetrafluoroethylene.Fluorinated fluorophores are of significant interests to improve their fluorescent performance.Several fluorinated fluorophores have been synthesized and applied to be chemical probes with improved photophysical properties.Dihydroxanthene(DHX)-Hemicyanine(HC)fused fluorophore is a family of newly developed near-infrared dyes.Due to their near-infrared emitting nature,DHX-HC dyes have high potential to be chemsensors with deep penetration in living organism and minimized damage to biological samples.Before our research,fluorinated DHX-HC fused fluorophores have been seldom studied.In this work,we developed divergent access to a library of fluorinated DHX-HC dyes through 6’-regioselective S_NAr reactions.We prepared 5’,6’,7’-trifluoro-dihydroxanthene(DHX)-hemicyanine(HC)fused scaffold as a precursor through two-steps reactions with 54%yield.From the reactions between 3,4,5-trifluoro-2-hydroxybenzaldehyde and 6-bromocyclohex-1-ene-1-carbaldehyde in DMF,we prepared trifluoro-dihydroxanthene-aldehyde in 61%yield.Then the trifluoro-dihydroxanthene-aldehyde reacted with indolium iodide in ethanol and formed to be target 5’,6’,7’-trifluoro-DHX-HC with 88%yield.We prepared 5’,6’,7’-trifluoro-DHX-HC in 10-gram scale with this synthetic route.Then we used morpholine as a model nucleophile and optimized the S_NAr reaction conditions,including base,solvent,temperature,and reaction time.After a detailed evaluation,a reaction carried out in pyridine at 80~oC for eight hours performed the best yield(61%).With this late-stage 6’-regioselective strategy,we treated 5’,6’,7’-trifluoro-DHX-HC precursor with a wide range of nitrogen,sulfur and selenium nucleophiles and prepared 6’-substituted 5’,7’-difluoro-DHX-HC dyes with yield 8-95%.We evaluated the photophysical performance of the twenty-three 5’,7’-difluoro DHX-HC dyes in different solutions.Comparing with their non-fluorinated analogs,the absorption bands of these 5’,7’-difluoro-DHX-HCs are broad and structureless.Confirmed by TD-DFT calculation,the two ortho-fluorine atoms could impede the presence of single absorbing species in solution.The sole 5’,7’-difluoro-DHX-HC that has similar absorption band as its fluorine-free analog is N-pyrrolidinyl-DHX-HC.It proved that the azolidine could avoid the steric interference of fluorine atoms and further inhibit the multiple conformers of these dyes in solution.As expectation,6’-N,N-dialkylamino-substituted 5’,7’-difluoro-DHX-HC emitted in the near-infrared region with emission wavelengths in the range of 709-747 nm.However,the quantum yields are low compared with their non-fluorinated counterparts.The eight 5’,7’-difluoro-DHX-HCs with N-aryl substituent or aryl thiol/selenol moieties are not fluorescent due to the lack of electro-donating groups.These dyes could be used as NIR dark quenchers.In summary,we described a synthetic route to a 5’,6’,7’-trifluoro-dihydroxanthene-hemicyanine as a precursor.A 6’-regioselective S_NAr strategy was developed and gave access to twenty-three 6’-substituted 5’,7’-difluoro-DHX-HC dyes.We also investigated their photophysical properties both experimentally and theoretically.