Unparalleled Ease of Access to a Library of Biheteroaryl Fluorophores via Oxidative Cross-Coupling Reactions: Discovery of Photostable NIR Probe for Mitochondria

Abstract

The development of straightforward accesses to organic functional materials through C-H activation is a revolutionary trend in organic synthesis. In this article, we propose a concise strategy to construct a large library of donor-acceptor-type biheteroaryl fluorophores via the palladium-catalyzed oxidative C-H/C-H cross-coupling of electron-deficient 2H-indazoles with electron-rich heteroarenes. The directly coupled biheteroaryl fluorophores, named Indazo-Fluors, exhibit continuously tunable full-color emissions with quantum yields up to 93% and large Stokes shifts up to 8705 cm(-1) in CH2Cl2. By further fine-tuning of the substituent on the core skeleton, Indazo-Fluor 3l (FW = 274; λem = 725 nm) is obtained as the lowest molecular weight near-infrared (NIR) fluorophore with emission wavelength over 720 nm in the solid state. The NIR dye 5h specifically lights up mitochondria in living cells with bright red luminescence. Typically, commercially available mitochondria trackers suffer from poor photostability. Indazo-Fluor 5h exhibits superior photostability and very low cytotoxicity, which would be a prominent reagent for in vivo mitochondria imaging.

Transition-Metal-Catalyzed C–H Bond Addition to Carbonyls, Imines, and Related Polarized π Bonds

“…These fluorescent properties have encouraged the preparation and study of other N -aryl-2 H -indazole derivatives and related structures. 59 …”

A General One‐Pot Synthesis of 2H‐Indazoles Using an Organophosphorus–Silane System

“…Unimpressed by the shortcomings of current synthetic methodologies, this framework is of well‐documented relevance as a pharmacophore within drugs such as niraparib and pazopanib (Figure ). In addition, the attractive fluorophoric properties of 2 H ‐indazoles were recently described in a systematic study that illustrated their diagnostic value as tools for cellular imaging in chemical biology investigations …”

Modern Synthetic Avenues for the Preparation of Functional Fluorophores

“…These approaches are limited by the ubiquity of C−H bonds but the recent discovery of new selectivity rules is enabling the rapid expansion of the field. For instance, CDCs have been used by You and co‐workers to tune donor–acceptor dyads by linking electron‐rich (e.g., furans, thiophenes) and electron‐poor heterocycles (e.g., indazoles) in regioselective oxidative couplings (Figure 5 H) 33. The resulting bis(heteroaryl) dyes (Indazofluors) display full‐color‐tunable emission (393–725 nm), high fluorescence quantum yields (up to 93 % in CH 2 Cl 2 , relative to rhodamine B),33 and could find applications as subcellular organelle markers.…”