Our group has reported several one-pot protocols for the synthesis of diaryliodonium salts, which have been recognized as attractive multi-purpose reagents in areas ranging from organic synthesis to materials chemistry. Over the years, we have identified limitations in the published protocols concerning synthesis of mixed electron-rich and electron-poor, as well as highly electron-poor diaryliodonium salts, as the corresponding starting materials are either too reactive or too unreactive. In this update, we discuss the underlying limitations concerning the stability and reactivity of the involved reagents and provide strategies to overcome these challenges through updated synthetic protocols. 

Diaryliodonium salts (Ar₂IX) have emerged as versatile multi-purpose reagents with desirable properties such as easy accessibility, low toxicity and applicability under mild and metal-free reaction conditions. Despite displaying broad utility in arylations of both carbon and heteroatom nucleophiles, the overall sustainability of these protocols is compromised by featuring poor atom economy due to the formation of stochiometric iodoarene byproducts. In this thesis, this imperative drawback was addressed by development of a novel class of diaryliodonium salts with unprecedented reactivity that prevents the formation of iodoarene waste by incorporating both aryl groups as well as the iodine-component into the final products. 

The first project concerns the development and design of ortho-fluorinated iodonium salts, where updated synthetic protocols were established to attain extensive salt scopes with diverse functionalities. The unique design of these reagents unveiled a cascade reaction whereby heteroatom-diarylated products were formed through concomitant nucleophilic aromatic substitution and intramolecular aryl transfer. The second project focuses on the applications of the ortho-fluorinated salts in diarylations of aliphatic amines, anilines, ammonia and water to attain industrially important diaryl- and triaryl amines as well as diaryl ethers (>100 examples). This atom-efficient methodology allows for transfer of two different aryl groups in a single step under mild and metal-free conditions, giving structurally diverse multi-arene products that would otherwise require expensive and time-consuming multi-step synthesis. 

The third project explores the potent combination of the diarylation strategy with the structural diversification of secondary aliphatic amines in the preparation of densely functionalized diarylamines. Cyclic amines constitute essential cornerstones in drug discovery and incorporation of such valuable moieties in Ar₂IX reagents is of considerable interest. By further exploiting the S_NAr reactivity of the ortho-fluorinated diaryliodonium salts, a previously inaccessible class of amino-functionalized Ar₂IX were prepared by reactions with cyclic amines. These N-functionalized reagents were utilized in a one-pot sequential arylation/ring opening pathway, where intramolecular arylation afforded diarylammonium salts in situ, which upon reaction with external nucleophiles underwent deconstructive C­-N functionalizations. The methodology enables atom- and step-economical access to value-added diarylamines with versatile functionalities at both the C- and N- terminal. 

The final project emphasizes the applicability of the diarylated products as versatile building blocks in various downstream functionalizations. The retention of the iodine-component enables diversification by a range of transition metal-catalysed cross-couplings, delivering products with increased structural complexity. The significance of the diarylation methodology was further demonstrated in the three-step synthesis of the drug molecule NMP-7. Two protocols were developed for transformation of the ortho-iododiaryl ethers into oxygen-bridged cyclic diaryliodonium salts and acyclic aryloxy salts. The synthetic utility of these unexplored Ar₂IX reagents was demonstrated in metal-free, chemoselective functionalizations of common nucleophiles. 

The diarylation and skeletal diversification of unstrained cyclic amines was exploited to expand and modify the favorable properties of this important substrate class with pivotal roles in drug discovery. Cyclic amines were employed in the synthesis of a novel class of amino-substituted diaryliodonium salts, which were converted to highly functionalized diarylamines through an atom-efficient one-pot N-arylation/ring opening reaction with external nucleophiles. The reaction proceeds through in situ formation of a diarylammonium intermediate that undergoes a nucleophilic ring opening by cleavage of the strong C−N bond. A wide variety of diarylamines was obtained through introduction of two different aryl groups of varied electronics, and the retained iodo-substituent enables downfield diversifications of the products. More than 20 nucleophiles, including amines, phenols, carboxylic acids, thiols and halides, were alkylated with high functional group tolerance, and the strategy proved efficient also in in late-stage functionalization of natural products and pharmaceuticals. 

N- and O-arylated compounds are prevalent in pharmaceuticals and materials, and efficient approaches for their synthesis are important. Herein, we present an efficient protocol for the diarylation of aliphatic amines and water with two structurally different aryl groups in one single step, yielding highly functionalized diaryl amines and ethers. We describe the synthesis of the required diaryliodonium salts and detail the procedure for the diarylation. The protocol is limited to use of unhindered amines and diaryliodonium salts with certain substituents.

The arylation of heteroatom nucleophiles is a central strategy to reach diarylated compounds that are key building blocks in agrochemicals, materials, and pharmaceuticals. Nucleophilic aromatic substitution is a classical tool for such arylations, and recent developments in hypervalent iodine-mediated arylations allow a wider scope of products. Herein, we combine the benefits of these strategies to enable an efficient and transition-metal-free difunctionalization of N-and O-nucleophiles with two structurally different aryl groups and to provide di-and triarylamines and diaryl ethers in one single step (>100 examples). The core of this strategy is the unique reactivity discovered with specifically designed fluorinated diaryliodonium salts, which unveils novel reaction pathways in hypervalent iodine chemistry. The methodology is suitable for diarylation of aliphatic amines, anilines, ammonia, and even water. It tolerates a wide variety of functional and protecting groups, with the retained iodine substituent easily accessible for derivatization of the products.

Two regioselective, high-yielding one-pot routes to oxygen-bridged cyclic diaryliodonium salts and ortho-aryloxy-substituted acyclic diaryliodonium salts are presented. Starting from easily available ortho-iodo diaryl ethers, complete selectivity in formation of either the cyclic or acyclic product could be achieved by varying the reaction conditions. The complimentary reactivities of these novel ortho-oxygenated iodonium salts were demonstrated through a series of chemoselective arylations under metal-catalyzed and metal-free conditions, to deliver a range of novel, ortho-functionalized diaryl ether derivatives. 

A transition metal-free N-arylation of primary and secondary amines with diaryliodonium salts is presented. Both acyclic and cyclic amines are well tolerated, providing a large set of N-alkyl anilines. The methodology is unprecedented among metal-free methods in terms of amine scope, the ability to transfer both electron-withdrawing and electron-donating aryl groups, and efficient use of resources, as excess substrate or reagents are not required.