No abstract

This work delineates a method for the modular synthesis of reagents that are capable of direct incorporation of difluoroalkyl groups onto heterocycles. The scope and generality of this method is exemplified with the difluoroethyl group (along with the introduction of a new reagent for difluoroethylation, DFES-Na) and a proof of principle is shown for a general synthesis of fluorinated heteroarylether bioisosteres.

The oxidative cleavage of olefins is an integral process that converts feedstocks into highvalue synthetic intermediates 1,2,3 . The most viable method to oxidatively cleave C-Cπ bonds in one chemical step is with ozone 4,5,6,7 , which however poses technical and safety challenges owing to the explosive nature of ozonolysis products 8,9 . Herein, we present a distinct approach to achieve oxidative cleavage of olefins using nitroarenes and purple light irradiation. We demonstrate that photoexcited nitroarenes are effective ozone surrogates that undergo facile radical [3+2] cycloaddition with olefins. The resulting "Ndoped" ozonide cycloadducts are safe to handle and lead to the corresponding carbonyl products under mild hydrolytic conditions. These features have enabled the controlled cleavage of all types of olefins in the presence of a broad array of commonly used organic functionalities. Furthermore, by harnessing electronic, steric, and mediated polar effects, the structural and functional diversity of nitroarenes has provided a modular platform to obtain site-selectivity in substrates containing more than one olefin.Olefins are feedstock materials harvested on ton-scale from petroleum and vegetable biomass routinely exploited by the bulk chemical industry to access oxygen-enriched synthetic intermediates 1,2,3 . Ozonolysis is a widely adopted method to achieve this and requires a specialised apparatus for the conversion of molecular oxygen (O2) into highly reactive ozone (O3) 6,7 . This species undergoes a [1,3] dipolar cycloaddition with the olefin converting a stable chemical into a high-energy 1,2,3-ozonide A from which cycloreversion is immediate. The consequent C-C σ-bond cleavage event generates carbonyl oxide B and carbonyl compound C which recombine to give 1,2,4-ozonide D. Depending on reaction solvent and work-up procedure, B or D can lead to aldehydes/ketones as well as carboxylic acids or alcohols 4,5 (Fig. 1a).Despite its attractive synthetic versatility, ozone toxicity (lethal at 5 ppm), explosivity, and extreme oxidising power (E0 = 2.07 V) raise critical safety, technical, and chemical concerns 8,9 .As a result, ozonolytic strategies are often challenging to translate into the fine chemical industry 10,11,12 , particularly in the discovery sector which heavily relies on parallel and highthroughput screening platforms 13 . Consequently, alternative strategies for olefin oxidation based on high-valent heavy-metal oxides have been devised. However, these approaches can yield mixtures of products of various oxidation degrees, and cause trace metal contaminations

Arylamines constitute the core structure of many therapeutic agents, agrochemicals, and organic materials. The development of methods for the efficient and selective construction of these structural motifs from simple building blocks is desirable but still challenging. We demonstrate that protonated electron‐poor O‐aryl hydroxylamines give aminium radicals in the presence of Ru(bpy)3Cl2. These highly electrophilic species undergo polarized radical addition to aromatic compounds in high yield and selectivity. We successfully applied this method to the late‐stage modification of chiral catalyst templates, therapeutic agents, and natural products.

Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen‐radicals to undergo strain‐release reaction with [1.1.1]propellane. This reactivity is facilitated by the electrophilic nature of these open‐shell intermediates and the presence of strong polar effects in the transition‐state for C−N bond formation/ring‐opening. With the aid of a simple reductive quenching photoredox cycle, we have successfully harnessed this novel radical strain‐release amination as part of a multicomponent cascade compatible with several external trapping agents. Overall, this radical strategy enables the rapid construction of novel amino‐functionalized building blocks with potential application in medicinal chemistry programs as p‐substituted aniline bioisosteres.