Synthesis of near-infrared fluorescent rhodamines via an S_NAr^H reaction and their biological applications

Abstract

Near-infrared (NIR) dyes are of great interest in biomedicine due to diminished interfering absorption and fluorescence from biological samples, reduced scattering, and enhanced tissue penetration depth. In this context, we report the synthesis of rectilinearly π-extended rhodamine dyes using a unique intramolecular nucleophilic substitution of aromatic hydrogen (SNArH) strategy. The strategy makes use of an SNArH reaction between a preorganized aromatic amino nitrogen and an electron-deficient carbon in the xanthylium ion. The SNArH reaction presented herein can be performed under mild conditions without a transition metal catalyst and can be expected to enable the preparation of a wide variety of π-extended near-infrared fluorescent rhodamine dyes. Using this strategy, seven rectilinearly π-extended rhodamines (RE1-RE7) that had fluorescence emission wavelengths in the near-infrared region were synthesized. RE1, RE3, and RE4 were lysosome targetable and showed good photostabilities. In addition, using dye RE1 as a precursor, we constructed a novel NIR fluorescent turn-on probe (RE1-Cu), which can be used for detecting Cu2+ in living cells, demonstrating the value of our NIR functional fluorescent dyes.

Recent Advances in Heterocyclic Nanographenes and Other Polycyclic Heteroaromatic Compounds

“…An alternative approach, employing nucleophilic aromatic substitution in the ring-forming step, was used by Zeng et al to prepare the NIR fluorescent rhodamine dye 183.4 . 361 183.4 showed a near-infrared emission at 830 nm, significantly red-shifted in comparison with conventional rhodamine dyes.…”

“… In this synthesis, Buchwald–Hartwig amination was presumed to precede the arylation step. An alternative approach, employing nucleophilic aromatic substitution in the ring-forming step, was used by Zeng et al to prepare the NIR fluorescent rhodamine dye 183.4 …”

Rational design of a large Stokes shift xanthene–benzothiozolium dyad for probing cysteine in mitochondria

“…Herein, in order to provide better solutions, based on the reports that an amplified dye molecule p-conjugated system can increase the emission wavelength and Stokes shift, 29,30 we decided to use heteroatom replacement and the extension of the p-conjugated system strategy at the same time looking forward to improve the emission wavelength and Stokes shift of the xanthene-benzothiozolium fluorophores. For the construction of the target fluorophore, a benzene ring was fused into the benzothiozolium moiety and the oxygen atom was replaced with the S atom in the xanthene moiety.…”

Desulfitative Sonogashira cross-coupling of thiopyronin for the synthesis of NIR arylacetylene-containing rhodamines

“…The conventional strategies to contribute to a bathochromic shift for NIR rhodamines mainly include alkylation of amino groups; 3 substitution of the O atom of pyronin; 4 and hybridization with other fluorophores. 5 To the best of our knowledge, there are few studies on changing the optical properties by modifying the 9 position of the pyronin core.…”