Markus R. Heinrich

Intermolecular Olefin Functionalisation Involving Aryl Radicals Generated from Arenediazonium Salts

This minireview is aimed at giving an overview of recent advances in olefin functionalisation reactions involving aryl radicals generated from arenediazonium salts. Based on the well-known Meerwein arylation, in which an aryl and a halogen substituent are coupled to an olefinic substrate, new reaction types have been developed that allow the introduction of a broad spectrum of other atoms and functional groups at the place of the original halogen atom and that are applicable to an extended range of olefinic substrates.

Synthesis of Amino‐ and Hydroxybiphenyls by Radical Chain Reaction of Arenediazonium Salts

A wide range of organometallic methods have been developed for the mild and efficient synthesis of biaryl compounds. In this context, addition reactions of aryl radicals to aromatic substrates have so far only rarely been applied. Complications in intermolecular radical aryl–aryl couplings occur as a result of the relatively slow addition of aryl radicals to common substrates such as substituted benzenes, which in turn gives rise to side reactions. Successful aryl–aryl couplings therefore often require special conditions; for example, the substrate is used as the solvent or the reaction is modified to an intramolecular conversion. Aryl–aryl couplings using arenediazonium salts A as precursors are known as Gomberg–Bachmann 11] or Pschorr reactions (Scheme 1). These reactions are complicated by the fact that a reductant is needed for the generation of radicals B and C, whereas oxidizing conditions are required for the rearomatization of the cyclohexadienyl intermediateE. 15] To date, only a few studies have proposed to employ the diazonium salt A both as the source of C and as an oxidant for intermediate E. Given that the reactivity of aryl radicals is more controlled in water than in most other organic solvents, 18] we decided to evaluate homolytic aromatic substitution reactions in aqueous solution. Our first results on the synthesis of aminoand hydroxybiphenyls are reported herein. For reasons of solubility and unambiguous regioselectivity, 4-chlorophenyldiazonium chloride (1a) and 1,4-phenylenediamine (2a) were chosen for the initial study (Table 1).

Radical Arylation of Phenols, Phenyl Ethers, and Furans

Radical arylations of para-substituted phenols and phenyl ethers proceeded with good regioselectivity at the ortho position with respect to the hydroxy or alkoxy group. The reactions were conducted with arenediazonium salts as the aryl radical source, titanium(III) chloride as the reductant, and diluted hydrochloric acid as the solvent. Substituted biaryls were obtained from hydroxy- and alkoxy-substituted benzylamines, phenethylamines, and aromatic amino acids. The methodology described offers a fast, efficient, and cost-effective new access to diversely functionalized biphenyl alcohols and ethers. Free phenolic hydroxy groups, aromatic and aliphatic amines, as well as amino acid substructures, are well tolerated. Two examples for the applicability of the methodology are the partial synthesis of a beta-secretase inhibitor and the synthesis of a calcium-channel modulator.

Oxidative Radical Arylation of Anilines with Arylhydrazines and Dioxygen from Air

Substituted 2-aminobiphenyls have been prepared from arylhydrazine hydrochlorides and anilines in biphasic radical arylation reactions with dioxygen from air as a most simple and readily available oxidant. Under optimized conditions, the free amino functionality of the aniline leads to high ortho:meta regioselectivities, now even for anilines bearing a donor substituent in the para position. Finally, the mild and metal-free new access to aminobiphenyls was shown to be applicable on a gram scale.

Regioselective radical arylation of anilines with arylhydrazines.

Substituted 2-aminobiphenyls have been prepared from arylhydrazines and anilines via radical arylation reactions under simple oxidative conditions. The strong directing effect of the free and unprotonated amino functionality leads to high regioselectivities, and anilines have been shown to be significantly better aryl radical acceptors than nitrobenzenes or phenyl ethers. The methodology is also applicable to phenols, which react best as phenolates under strongly basic conditions. Finally, radical arylation reactions of anilines and anilinium salts under various conditions have for the first time demonstrated that regioselectivity can also be controlled through the rearomatization step and that the addition of an aryl radical to a substituted benzene might even be reversible.

The Gomberg-Bachmann reaction for the arylation of anilines with aryl diazotates.

Simply aqueous sodium hydroxide is sufficient to exclude ionic side reactions and to prepare 2-aminobiphenyls from aryl diazotates and anilines through a new variant of the Gomberg-Bachmann reaction (see scheme). The metal-free reaction under basic conditions allows to exploit the highly radical-stabilizing effect of the anilines free amino function for the first time, which leads to a so far unreached regioselectivity.

Hydroxy‐ and Aminophenyl Radicals from Arenediazonium Salts

Arenediazonium salts and their synthetic applications have a long history in both ionic and radical chemistry. Starting with the pioneering work by Peter Griess in the 1860s, arenediazonium salts became well-known through several prominent name reactions among which the Sandmeyer, Meerwein, Pschorr, Gomberg-Bachmann, and the Japp-Klingemann transformations. Given the large number of reports published in this field in the past 150 years, it is surprising that there is one group of diazonium ions for which radical reactions remained practically unknown. Driven by the interest to find out whether this exclusion is due to the unique reactivity of the hydroxy-substituted aryl radicals 1 and 2, or is rather a consequence of special properties of the related arenediazonium ions 3 and 4 (e.g., the possible formation of quinonediazides), we revisited the chemistry of these compounds and their reactive intermediates. Herein, we summarized our first results.

Nucleophilic Substitutions and Radical Reactions of Phenylazocarboxylates

tert-Butyl phenylazocarboxylates are versatile building blocks for synthetic organic chemistry. Nucleophilic substitutions of the benzene ring proceed with aromatic amines and alcohols under mild conditions. The attack of aliphatic amines may be directed to the aromatic core as well as to the carbonyl unit leading to azocarboxamides. The benzene ring can further be modified through radical reactions, in which the tert-butyloxycarbonylazo group enables the generation of aryl radicals at either elevated temperatures or under acidic conditions. Radical reactions include oxygenation, halogenation, carbohalogenation, carbohydroxylation, and aryl-aryl coupling.

Base-Induced Radical Carboamination of Nonactivated Alkenes with Aryldiazonium Salts

A new transition-metal-free version of the Meerwein arylation has been developed. The key feature of this carboamination-type reaction is the slow base-controlled generation of aryl radicals from aryldiazonium tetrafluoroborates, so that a sufficient quantity of diazonium ions remains to enable efficient trapping of the alkyl radical adduct resulting from aryl radical addition to the alkene. Under strongly basic conditions, diazoanhydrides are likely to take over the role of the nitrogen-centered radical scavengers.

Development of flavonoid-based inverse agonists of the key signaling receptor US28 of human cytomegalovirus.

A series of 31 chalcone- and flavonoid-based derivatives were synthesized in good overall yields and screened for their inverse agonist activity on the US28 receptor of human cytomegalovirus (HCMV). With one exception (e.g., 2-(5-bromo-2-methoxyphenyl)-3-hydroxy-4H-chromen-4-one), halogen-substituted flavonoids were typically more potent inverse agonists than their related hydro derivatives. While toxicity could be used to partially explain the inverse agonist activity of some members of the series, 5-(benzyloxy)-2-(5-bromo-2-methoxyphenyl)-4H-chromen-4-one (11b) acted on the US28 receptor as a nontoxic, inverse agonist. The full inverse agonism (efficacy, -89%) and potency (EC50 = 3.5 μM) observed with flavonoid 11b is especially important as it provides both a new tool to study US28 signaling and a potential platform for the future development of HCMV-targeting drugs.