The catalytic alkylation of amines with alcohols is a highly atom-economical approach that produces water as the sole by-product. Existing catalytic systems lack generality and are primarily applicable to electron-poor amines or to non-oxidizable amines, such as anilines. The outstanding effectiveness of an Ir-NHC catalyst in forming C−N bonds from alcohols and amines, both aliphatic and aromatic, is presented here. The catalyst performs remarkably under mild conditions, even at room temperature, attaining complete selectivity in all tested cases toward monoalkylation, even for challenging aliphatic amines, and under base-free conditions. Thorough mechanistic investigation to understand the outstanding activity and selectivity, combining experimental, theoretical, and both in situ and ex situ X-ray absorption spectroscopy (XAS) studies, are presented.

A novel iron-catalyzed borylation of propargylic acetates leading to allenylboronates has been developed. The method allows the preparation of a variety of di-, tri- and tetrasubstituted allenylboronates at room temperature with good functional group compatibility. Stereochemical studies show that an anti-S_N2’ displacement of acetate by boron occurs; this also allows transfer of chirality to yield enantiomerically enriched allenylboronates. The synthetic utility of this protocol was further substantiated by transformations of the obtained allenylboronates including oxidation and propargylation. 

The mechanism of dehydrogenation of amines catalyzedby (cyclopentadienone)ironcarbonyl complexes was studied by means of kinetic isotope effect(KIE) measurements, intermediate isolation, and density functionaltheory calculations. The (cyclopentadienone)iron-amine intermediateswere isolated and characterized by H-1 and C-13 NMR spectroscopy as well as X-ray crystallography. The isolatediron-amine complexes are quite stable and undergo a formal beta-hydride elimination to produce imine and iron hydride complexes.The KIEs observed for the iron-catalyzed dehydrogenation of 4-methoxy-N-(4-methylbenzyl)aniline are in accordance with stepwisedehydrogenation. The density functional calculations corroborate astepwise mechanism involving a rate-determining hydride transfer fromamine to iron to yield a metal hydride and an iminium intermediate,followed by a proton transfer from the iminium ion to the oxygen ofthe cyclopentadienone ligand.

Unnatural amino acids are valuable building blocks with numerous applications. Here, we present a quantitative technique for accessing mono-N-functionalized amino acids directly from unprotected substrates using alcohols as alkylating agents and an NHC-Ir(III) catalyst. We detail specific steps for catalyst preparation and application, as well as for catalyst recycling. The protocol excludes a few amino acids (l-cysteine, l-lysine, and l-arginine) and secondary alcohols.

Dr. Aitor Bermejo López graduated with a degree in chemistry from the Universidad Autónoma de Madrid. He completed his master’s studies and subsequently obtained a doctoral degree in organic chemistry from Stockholm University with Prof. Belén Martín-Matute. He gained expertise in organometallic catalysis while focusing on the development of new transformations and on the study of their mechanisms. He defended his doctoral thesis recently this year and is eager to see what the future has in store and to grow as a scientist.

The present thesis describes the applicability of two different iridium(III) complexes for C-O and C-N bond forming reactions. The different projects described in this work are united by the use of an iridium catalyst bearing a functionalized N-heterocyclic carbene ligand. These catalysts operate through a hydrogen transfer mechanism to afford the desired products. This approach gives access to a variety of valuable products in a sustainable and atomeconomical manner, generating water as the only byproduct.

In Chapter 1, a general introduction to catalysis, followed by a more detailed description of organometallic complexes and their use in hydrogen transfer reactions is described. An overview of different mechanistic studies that have been employed within this thesis is also provided.

Chapter 2 describes the use of an alkoxy-functionalized iridium-NHC complex, previously reported by our group, on cyclodehydration reactions (Paper I). A range of cyclic ethers are obtained from the corresponding diol compounds. Mechanistic studies confirmed an unexplored hydrogen transfer pathway to be operating for the majority of the substrates.

In Chapter 3, a new amino-functionalized iridium-NHC catalyst is designed and synthesized, aiming at improving the reactivity compared to previous reports. Then, its outstanding efficiency on carbon-nitrogen bond forming reactions is depicted in different protocols (Papers II, III and IV).

Paper II achieves the base-free and selective mono-N-alkylation of amines with alcohols mostly at room temperature. Mechanistic studies are performed to gain a better understanding of the catalytic cycle by combining experimental and in silico studies.

In Paper III, the use of this catalyst to access N-modified amino acids is described. Excellent group tolerance allowed for the synthesis of more than 100 compounds. Moreover, quantitative yields are obtained in all cases without the need of tedious derivatization/purification steps. In addition, convenient scalability, recyclability and deuterium labelling studies are also presented. Further applicability of these compounds as high-value building blocks for the synthesis of N-modified peptides is demonstrated.

In Paper IV, the catalyst is used for the direct mono-N-alkylation of a range of aminosugars with alcohols. The method is developed to be applied on unprotected carbohydrates, that enables to access these important organic molecules in a direct, and thus sustainable, manner, avoiding unnecessary protection and deprotection steps.

A new Ir(III)-NHC catalyst is reported that shows remarkable activity in the N-alkylation of unprotected amino acids. The catalytic system gives excellent selectivity toward monoalkylated α-amino acids and a high degree of retention of stereochemistry. A wide range of unprotected nonnatural amino acids have been prepared. These compounds represent an array of building blocks that could be used for the direct synthesis of peptidomimetics. The synthesis of amino-acid-based surfactants is also reported. This catalytic method gives the amino acid products in quantitative yield; hence, tedious purifications by derivatization are therefore avoided. Furthermore, although the catalyst is a homogeneous metal complex, it can be recycled and reused for several runs. This also contributes to the efficiency and sustainability of the method.

Herein we disclose an iron-catalyzed cross-coupling reaction of propargyl ethers with Grignard reagents. The reaction was demonstrated to be stereospecific and allows for a facile preparation of optically active allenes via efficient chirality transfer. Various tri- and tetrasubstituted fluoroalkyl allenes can be obtained in good to excellent yields. In addition, an iron-catalyzed cross-coupling of Grignard reagents with α-alkynyl oxetanes and tetrahydrofurans is disclosed herein, which constitutes a straightforward approach towards fully substituted β- or γ-allenols, respectively.

Palladium-metalated PCN-222 enables the aerobic photo-oxidative cross-condensation of anilines with benzylic amines yielding a series of linear and cyclic imines. The reaction is very efficient under mild conditions, which allows the isolation of simple, yet elusive, intermediates such as 2-(benzylideneamino)-aniline and 2-(benzylideneamino)phenols. Recyclability studies show excellent activity and selectivity after five runs. The methodology was successfully applied for the synthesis of an antitumor agent (PMX-610).

1,4- and 1,5-diols undergo cyclodehydration upon treatment with cationic N-heterocyclic carbene (NHC)-Ir-III complexes to give tetrahydrofurans and tetrahydropyrans, respectively. The mechanism was investigated, and a metal-hydride-driven pathway was proposed for all substrates, except for very electron-rich ones. This contrasts with the well-established classical pathways that involve nucleophilic substitution.