Boryl Radicals Enabled a Three-Step Sequence to Assemble All-Carbon Quaternary Centers from Activated Trichloromethyl Groups

Abstract

The construction of diversely substituted all-carbon quaternary centers has been a longstanding challenge in organic synthesis. Methods that add three alkyl substituents to a simple C­(sp3) atom rely heavily on lengthy multiple processes, which usually involve several preactivation steps. Here, we describe a straightforward three-step sequence that uses a range of readily accessible activated trichloromethyl groups as the carbon source, the three C–Cl bonds of which are selectively functionalized to introduce three alkyl chains. In each step, only a single C–Cl bond was cleaved with the choice of an appropriate Lewis base–boryl radical as the promoter. A vast range of diversely substituted all-carbon quaternary centers could be accessed directly from these activated CCl3 trichloromethyl groups or by simple derivatizations. The use of different alkene traps in each of the three steps enabled facile collections of a large library of products. The utility of this strategy was demonstrated by the synthesis of variants of two drug molecules, whose structures could be easily modulated by varying the alkene partner in each step. The results of kinetic and computational studies enabled the design of the three-step reaction and provided insights into the reaction mechanisms.

Lewis Base–Boryl Radicals Enabled Borylation Reactions and Selective Activation of Carbon–Heteroatom Bonds

“…Chem. Soc.20221441527515285 . A three-step sequence to assemble all-carbon quaternary centers from readily accessible trichloromethyl groups was reported, wherein the excellent chemoselectivity was achieved by the rational choice of boryl radical precursor in each step.…”

“…In addition to trifluoromethyl groups, we further aimed to extend this strategy to successively functionalize the three C–Cl bonds of trichloromethyl groups, thereby accessing all-carbon quaternary centers . Such a unit is a fundamental constituent of some pharmaceuticals and functional materials, wherein its construction still relies on lengthy synthetic routes.…”

Boron-Methylated Dipyrromethene as a Green Light Activated Type I Photoinitiator for Rapid Radical Polymerizations

“…Inspired by UV-light induced β-scission observed in N -heterocyclic carbene boranes, − blue-light (440 nm) induced β-scission of boracenes, and recent utility of electron-rich boryl radicals as nucleophiles in synthetic chemistry − it was hypothesized that boron-functionalized variants of BODIPY fluorophores could provide a novel Type I photoinitiator platform for rapid and efficient free radical polymerization. Moreover, it was recently shown that boron-ethylated BODIPY could be used as a turn-on fluorescent sensor upon irradiation with a high intensity blue laser (488 nm, ≥28 W/cm 2 ), resulting in substitution of the ethyl functionality, although the mechanism was not reported .…”

Formation of C–B, C–C, and C–X Bonds from Nonstabilized Aryl Radicals Generated from Diaryl Boryl Radicals

“…Radicals, which can be generated from many feedstock chemicals, are among the most fundamental intermediates in synthetic chemistry and have become useful tools for developing novel methodologies. − With the development of organoboron chemistry, boron-centered radicals have become more and more attractive, but their synthetic applications remain limited. − For example, the applications of neutral boryl radicals, which are three-center–five-electron radicals, are limited because of their extreme electron deficiency (Figure A). In contrast, four-center–seven-electron boryl radicals ligated with a Lewis base (usually a carbene, a phosphine, or an amine) are relatively stable and have been extensively studied. − These Lewis base-based boryl radicals are known to react with alkenes and heteroaromatic rings, and such reactions have been used to modify drug molecules. − In recent years, the groups of Wang and Li have reported some elegant uses of amine-based boron free radicals as catalysts. , In 2022, Xia’s group reported a method for alkyl radical generation by direct splitting of the C–O bonds of alcohol–boron radical intermediates; in these reactions, various alcohols were successfully used as alkyl radical precursors (Figure B).…”