Selective synthesis of substituted amino-quinoline derivatives by C-H activation and fluorescence evaluation of their lipophilicity-responsive properties

Yasufumi Fuchi,Satoru Karasawa,Ryusuke Hagihara,Kohei Ohyama,Minaki Kohno,Akihiro Mizutani,Masaomi Sakuma,Koichi Hamada

doi:10.1038/s41598-019-53882-z

Abstract

Push-pull type fluorescent amino-quinoline derivatives (TFMAQ) bearing phenyl aromatic groups in the 8-position (TFMAQ-8Ar series) were synthesized via palladium-catalyzed C-H activation reaction in short steps. The N-arylation or C-H activation reactions were selectively controlled with high yield by combinations of palladium and phosphine ligands. The TFMAQ-8Ar analogues exhibited fluorescent solvatochromism in non-polar and polar solvents. In non-polar solvent, the absolute fluorescence quantum yield was high, wheareas the fluorescence was almost quenched in polar solvent. The TFMAQ-8Ar derivatives also showed high fluorescence emission at solid state owing to the planar structure between the quinoline ring and phenyl ring at the 7-amino group, as demonstrated by X-ray crystal structure analysis. The fluorescence imaging of 3T3-L1 cell using TFMAQ-8Ar derivatives was performed by confocal laser microscopy. Strong and specific emissions at lipid droplets were observed owing to the accumulation of TFMAQ-8Ar derivatives. Therefore, we propose that the TFMAQ-8Ar derivatives should become a versatile fluorescence probe for the live imaging of lipid droplets.

Highlights

Fluorescence molecules with electron-donor groups and electron-withdrawing groups in a π-conjugated system are used in some biological analysis[1,2]
In the synthesis of TFMAQ-7,7-diAr compound (2) from TFMAQ-7Ar (1), we discovered an interesting side-product, in which 8-position C-H was substituted by an aromatic group (TFMAQ-7,8-diPh, 3) despite non-substitution in the N7-position when conducted under Buchwald–Hartwig cross-coupling reaction conditions (Fig. 1A)
Since the aryl group in the TFMAQ 8-position is expected to be twisted against the quinoline plane, the fluorescence properties will shift depending on the twisted-intramolecular charge transfer (TICT) state[29,30]

Summary

Introduction

Fluorescence molecules with electron-donor groups and electron-withdrawing groups in a π-conjugated system are used in some biological analysis[1,2]. Nitrobenzoxadiazole derivatives and dansyl derivatives are representative push-pull type fluorescence groups with a bicyclic skeleton[3,4,5] Such molecules with both donor and acceptor groups in an aromatic ring generally have a solvatochromic effect on UV-Vis absorption and the fluorescence emission of the solvent environment along with changes in the intramolecular charge transfer (ICT) state[6,7]. The TFMAQs were derivatized to phenyl aromatic-substituted amine analogues to investigate the photophysical properties at solid state[25,26] These derivatives were found to have some crystal polymorphs, and emitted fluorescence by external stimuli such as grinding at solid state accompanied by conformational changes. By applying the lipophilicity-responsive fluorescence property of TFMAQ-8Ar compounds, cellular fluorescence imaging of differentiated 3T3-L1 cells was performed to detect intracellular LDs (Fig. 1B)

Methods

Findings

Discussion

Conclusion