Alkali metal alkoxides have long been known to cause hydrodehalogenation of aryl halides; this conversion of aryl halides to arenes happens when the reactions are conducted in appropriate solvents (with weak C-H bonds). More recently, when aryl halides are heated with alkoxides in arene solvents, coupling to arenes occurs. Both of these reaction types are known to involve aryl radical intermediates. The consensus has been that alkali metal alkoxides undergo electron transfer to aryl halides to form radicals, but crucial evidence has been missing. We now refute this proposal and show through deuterium isotope studies that the deprotonation of the substrates leads to benzynes that initiate radical chemistry. Surprisingly, o-, m-, p- and, in appropriate cases, r- (remote) benzynes are simultaneously formed. During reactions with potassium tert-butoxide, we observed for the first time low-level methylation of arenes, resulting from methyl radicals derived from tert-butoxide. Although methyl radicals could, in principle, arise by electron transfer from tert-butoxide ions, followed by known radical fragmentation, we show that a different, previously unreported mechanism applies.

ABSTRACT Reaction of KO t Bu with haloarenes in arene solvent leads to the formation of biaryls through radical intermediates, and we recently (2026) showed that the radical chemistry is initiated by the formation of benzynes. Our original studies (2014) compared the reactivity of iodobenzene and 2‐iodo‐ m ‐xylene; the latter substrate cannot form o ‐benzynes. Whereas iodobenzene led to the formation of biaryls (40%), for 2‐iodo‐ m ‐xylene this was suppressed almost to 0%. However, in the intervening time, we came to suspect that the iodoxylene was not an ideal substrate due to the potential reactivity of the Ar‐Me groups both to base and to hydrogen atom abstraction reactions. We have now examined two new substrates where the Ar‐Me groups are replaced by Ar‐Ph groups. These substrates cause much more efficient initiation of radical chemistry, arising from the formation of p ‐ and m ‐ benzynes through the reaction of iodobenzenes with base. Importantly, these substrates allow assessment of the role of the Ar‐Me groups in 2‐iodo‐ m ‐xylene in suppressing radical chemistry.

Reaction of diarylmethanes with the Grubbs-Stoltz reagent (KOtBu + Et3SiH) using THF as solvent led to diarylcyclopentanes through an unprecedented double-alkylation reaction, with four of the carbons of the cyclopentane coming from THF. In like manner, reaction of diarylmethanes with the same reagent in 1,4-dioxane as solvent led to double-alkylation to form diarylcyclopropanes, with two of the cyclopropane carbons coming from 1,4-dioxane. Monoalkylated substrates that were likely intermediates on the dialkylation pathway were subjected to the same conditions, leading to cyclisations to form cyclopentanes and cyclopropanes. The cyclisation chemistry also extended to formation of monoarylcyclopropanes from reaction of the corresponding benzylpotassium reagents with ethers, alcohols, sulfides, sulfoxides and sulfones.

The azaindane motif is present in a number of drug candidates and combines the benefits of both a high sp3-fraction and an heteroaromatic ring. However, only a limited number of efficient approaches for the elaboration of this motif have been reported, and very few are flexible enough to enable the fast generation of analogues. Here we report the exploration of a convergent process for the construction of a variety of azaindanes and related semi-saturated fused heterocycles from an heteroaromatic triphenylpyridinium (Katritzky Salt) and an alkene coupling partner. In this process, two new C─C bonds are formed in a single step involving the activation of a pyridine-containing Katritzky salt under visible light irradiation in acidic conditions without the use of additional reductant/oxidant or photocatalyst. Under these operationally simple conditions, a variety of functional groups are tolerated, but the outcome of the reaction is dependent on the electronic nature of the pendant heterocycle and the alkene reaction partner. To help the exploration of future substrates, guidelines are established to predict the outcome of the reaction. Additionally, mechanistic studies shed light on the role played by the acid additive as well as the triphenylpyridine by-product in this process.

Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne, tert-butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1 electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3-trifunctionalised BCPs through lithium-halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2-electron “late stage” approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto-unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched “chiral-at-BCP” bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation.

This paper reports the first examples of ground state radical-mediated intramolecular C-H amination to afford 1-methyl-1,2,3,4-tetrahydroquinolines from N-2,4-dinitrophenoxy derivatives of arylpropylamines. Whereas the photoactivation of N-2,4-dinitrophenoxyamines for intermolecular reactions has been established, ground state chemistry provides the desired cyclization products in moderate to excellent yields using Ru(bpy)3Cl2 (42-95% yields) under acidic conditions under an air atmosphere.

An aryl radical assay is used to provide information about the formation of aryl radicals from aryl halides in coupling reactions to arenes in the presence of palladium sources and under LED irradiation (lambda = 456 nm). The assay uses 2-haloxylenes as substrates. Aryl radical formation is indicated both by a defined product composition and by signature deuterium isotope effects. Comparison with recently published results for corresponding ground state palladium-catalysed reactions shows three principal differences: (i) in the photoactivated reactions, evidence supports the formation of aryl radical intermediates with all the phosphine ligands tested, in contrast to thermal ground-state chemistry where only specific ligands had encouraged this pathway, while others had promoted a non-radical coupling mechanism; (ii) oxidative addition complexes that are formed from reaction of Pd(0) sources with aryl halides reacted under photoactivation to form biaryl coupled products through radical intermediates, in contrast to their behaviour under thermal activation;. (iii) the photoreactions work well with mild bases like Cs2CO3, while the thermal reactions required KOtBu as base due to the different roles for base under the thermal versus photochemical mechanisms.

In the presence of appropriate aryl halides, electron transfer occurs from KOtBu to form tert-butoxyl radicals that can fragment into methyl radicals. In support of electron transfer, we report the first observation of methylated arene products, arising from attack by these methyl radicals. When KOtBu is replaced by KOC(Et)3, ethyl radicals are correspondingly trapped. The conversion of KOtBu to methyl radicals happens in the presence of haloarene substrates. The reactions are not light-dependent. We illustrate the scope of the KOtBu-promoted aryl radical formation with a range of substrates that includes haloanthracenes, dihaloanthracenes, a dihalonaphthalene, and a dihalobenzene.

Reaction of benzene with potassium metal + potassium salts leads to formation of biphenyl and dihydrobiphenyls via dimerization of arene radical anions. Sodium salts are much less effective.

The idea that three different free radicals could be used together to carry out specific steps in a chemical reaction has long been implausible. A ‘radical sorting’ strategy now achieves this feat to make organic molecules. A ‘radical sorting’ strategy for organic synthesis.

We report the site-selective α-aryloxyalkyl C-H cyanation and allylation of aryl alkyl ethers using an acridinium photocatalyst with phosphate base under LED irradiation (456 nm). Oxidation of the aryl alkyl ether to its corresponding radical cation by the excited stated photocatalyst allowed facile deprotonation of the ArOC(sp3)-H bond to afford an α-aryloxyalkyl radical, which was trapped with sulfone substrates, resulting in expulsion of a sulfonyl radical and formation of allylated or cyanated products.

Aryl halides are efficiently coupled to benzene using air-stable Ni(COD)(DQ) (COD = 1,5-cyclooctadiene, DQ = duroquinone) and KOtBu, without additional ligands. Mechanistic evidence suggests that Ni(COD)(DQ) and KOtBu act as an initiation source, forming aryl radicals that then react with the arene via base-assisted homolytic aromatic substitution.

The combination of modern radical generation strategies and the radical C-H functionalisation of heteroaromatics (the Minisci reaction) offers attractive routes to the preparation of complex fused heteroaromatic compounds. In this work, the one-step preparation of a trifunctionalised spiro-azaindane was investigated through a radical cascade route. In an effort to determine the most efficient approach, this cascade was initiated by 4 different radical precursors, in varying yields, adapting recently developed protocols. The best results were achieved using a triphenylpyridinium salt (Katritzky salt) under visible light irradiation.

The functionalisation of C–H bonds has been an enormous achievement in synthetic methodology, enabling new retrosynthetic disconnections and affording simple synthetic equivalents for synthons. Hydrogen atom transfer (HAT) is a key method for forming alkyl radicals from C–H substrates. Classic reactions, including the Barton nitrite ester reaction and Hofmann–Löffler–Freytag reaction, among others, provided early examples of HAT. However, recent developments in photoredox catalysis and electrochemistry have made HAT a powerful synthetic tool capable of introducing a wide range of functional groups into C–H bonds. Moreover, greater mechanistic insights into HAT have stimulated the development of increasingly site-selective protocols. Site-selectivity can be achieved through the tuning of electron density at certain C–H bonds using additives, a judicious choice of HAT reagent, and a solvent system. Herein, we describe the latest methods for functionalizing C–H/Si–H/Ge–H bonds using indirect HAT between 2018–2023, as well as a critical discussion of new HAT reagents, mechanistic aspects, substrate scopes, and background contexts of the protocols.

Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range of photochemical applications. Taylor-Couette (vortex, dynamically mixed) reactors have been reported to have intensified mixing and have been used with heterogeneous systems. Our photochemical workflow has previously been demonstrated for the development of a photochemical Wohl-Ziegler process and scale-up in flow using a plug flow reactor (PFR). In this work, a 20 mL dynamically mixed Autichem, Ltd. prototype photochemical DART reactor (Taylor-Couette reactor) was paired with four custom Kessil PR160L 400 nm lamps. The reactor was evaluated as a 500 g scale-up option for the bromination of ethyl 4-methylbenzoate. Herein we describe our workflow moving from a Pacer International Photochemistry LED Illuminator (HTS system) to the photochemical DART reactor in the scale-up of the synthesis of ethyl 4-(bromomethyl)benzoate via a radical bromination process.

Evidence is presented for coupling through an aryl radical mechanism for a number of nickel sources.

An assay for aryl radicals, formed under basic conditions, emerges from the anomalous BHAS chemistry of substrate 7.

Palladium salts and complexes were tested separately and in the presence of added ligands as potential sources of aryl radicals in ground-state coupling reactions of aryl halide with arenes under basic conditions (KOtBu). Our recently developed assay for aryl radicals was employed to test for aryl radicals. In this assay, aryl radicals derived from the test substrate, 1-iodo-2,6-dimethylbenzene 7, undergo base-promoted homolytic aromatic substitution (BHAS) with benzene to produce 2,6-dimethylbiphenyl 8 and biphenyl 9 in an approximately 1:4 ratio as well as m-xylene 10. The biphenyl arises from a diagnostic radical transfer reaction with the solvent benzene. Using substrate 7 with a range of Pd sources as potential initiators led to formation of 8, 9, and 10 in varying amounts. However, when any one of a range of diphosphinoferrocenes (e.g., dppf or dippf) or BINAP or the monophosphine, diphenylphosphinoferrocene, was added as a ligand to Pd(OAc)2, the ratio of [2,6-dimethylbiphenyl 8: biphenyl 9] moved decisively to that expected from the BHAS (radical) pathway. Further studies were conducted with dppf. When dppf was added to each of the other Pd sources, the ratio of coupled products was also diverted to that expected for radical BHAS chemistry. Deuterium isotope studies and radical trap experiments provide strong additional support for the involvement of aryl radicals. Accordingly, under these ground-state conditions, palladium sources, in the presence of defined ligands, convert aryl iodides to aryl radicals. A rationale is proposed for these observations.

Herein, we report the decarboxylative Minisci heteroarylation of bicyclo[1.1.1]pentane (BCP) and 2-oxabicyclo[2.1.1]hexane (oBCH) derivatives at the bridge positions. In an operationally simple, photocatalyst-free process, free bridge carboxylic acids are directly coupled with nonprefunctionalized heteroarenes to provide rare examples of polysubstituted BCP and oBCH derivatives in synthetically useful yields. Additionally, the impact of the BCP core on the physicochemical properties of a representative example compared to those of its all-aromatic ortho- and meta-substituted analogues is evaluated.