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.

A transition metal-free approach for the N-arylation of amino acid derivatives has been developed. Key to this method is the use of unsymmetric diaryliodonium salts with anisyl ligands, which proved important to obtain high chemoselectivity and yields. The scope includes the transfer of both electron deficient, electron rich and sterically hindered aryl groups with a variety of different functional groups. Furthermore, a cyclic diaryliodonium salt was successfully employed in the arylation. The N-arylated products were obtained with retained enantiomeric excess.

This thesis concerns the development of metal-free arylation procedures using diaryliodonium salts, a non-toxic and versatile electrophilic arylating reagent, with applications to synthesize biologically relevant targets.

The first part describes a transition metal-free formal synthesis of phenoxazine with an O-functionalization of a certain phenol as a key step. Using a designed, unsymmetrical diaryliodonium salt, O-arylation provided an ortho-disubstituted diaryl ether which was cyclized to acetyl phenoxazine. An unusually stable iodine(III) intermediate was observed by NMR which could be converted to the product upon heating or applying a longer reaction time. This finding has an impact on the general understanding of ligand coupling mechanism which diaryliodonium salts follow.

The second and third part describes arylation of nitrogen nucleophiles. A general N-arylation of aliphatic amines under mild conditions was developed. The reaction has a broad substrate scope with a great variety in acyclic and cyclic primary and secondary amines, as well as diaryliodonium salts. The developed protocol is applicable for aryl transfer of both electron-poor and electron-rich aryl groups, the latter delivering products that had previously not been synthesized in a transition metal-free manner.

The successful N-arylation methodology was subsequently broadened to allow N-arylation of amino acid derivatives, resulting in a more general method to access biologically interesting compounds in a metal-free fashion which has never been reported in combination with diaryliodonium salts. The reaction could transfer a variety of aryl groups without compromising the stereocenter of the amino acid ester.

The last part describes the S-arylation of thioamides, resulting in the formation of thioimidates, a relatively unstudied class of compounds where the majority of the formed products are novel. Both electron-rich and electron-poor aryl groups could be transferred with high chemoselectivity and a large ortho-effect was observed. Furthermore, when examining this arylation procedure with cyclic thioamides, a different trend was observed and N-arylated thioamides were isolated.

A transition metal-free formal synthesis of phenoxazine is presented. The key step of the sequence is a high-yielding O-arylation of a phenol with an unsymmetrical diaryliodonium salt to provide an ortho-disubstituted diaryl ether. This species was cyclized to acetylphenoxazine in moderate yield. The overall yield in the three-step sequence is 72% based on recovered diaryl ether. An interesting, unusually stable iodine(III) intermediate in the O-arylation was observed by NMR and could be converted to the product upon longer reaction time.

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.

Reactions of secondary thioamides with diaryliodonium salts under basic, transition metal-free conditions resulted in chemoselective S-arylation to provide aryl thioimidates in good to excellent yields. Equimolar amounts of thioamide, base and diaryliodonium salt were sufficient to obtain a diverse selection of products within short reaction times. Reactions with thiolactams delivered N-arylated thioamides in good yield at room temperature.

A Mo(CO)(6) (molybdenumhexacarbonyl) catalyzed reductive functionalization of amides to afford 5-amino substituted 4,5-dihydroisoxazoles is presented. The reduction of amides generates reactive enamines, which upon the addition of hydroximinoyl chlorides and base undergoes a 1,3-dipolar cycloaddition reaction that gives access to the desired heterocyclic compounds. The transformation of amides is highly chemoselective and tolerates functional groups such as nitro, nitriles, esters, and ketones. Furthermore, a versatile scope of 4,5-dihydroisoxazoles derived from a variety of hydroximinoyl chlorides and amides is demonstrated.

Herein, a design of a biohybrid catalyst is described, consisting of Pd nanoparticles and a cross-linked network of aggregated lipase B enzyme of Candida antarctica (CalB CLEA) functioning as an active support for the Pd nanoparticles. Both entities of the hybrid catalyst showed good catalytic activity. The applicability was demonstrated in a one-pot reaction, where the Pd-catalyzed cycloisomerization of 4-pentynoic acid afforded a lactone that serves as an acyl donor in a subsequent selective enzymatic kinetic resolution of a set of sec-alcohols. The catalyst proved to be robust and could be recycled five times without a significant loss of activity.