Green approach to Palladium Cross-Coupling reactions and development of new methodologies based on highly abundant metals

Transition metal catalyzed cross-coupling reactions represent among the most versatile and useful tools in organic synthesis for the carbon-carbon (C-C) bond formation and have a prominent role in both the academic and pharmaceutical segments. Among them, palladium catalyzed cross-coupling reactions are currently the most versatile. In this thesis, the applications, impact and development of green palladium cross-coupling reactions are discussed. Specifically, we discuss the translation of the Twelve Principles of Green Chemistry and their applications in pharmaceutical organometallic chemistry to stimulate the development of cost-effective and sustainable catalytic processes for the synthesis of active pharmaceutical ingredients (API). The Heck-Cassar-Sonogashira (HCS) and the Suzuki-Miyaura (SM) protocols, using HEP/H2O as green mixture and sulfonated phosphine ligands, allowed to recycle and recover the catalyst, always guaranteeing high yields and fast conversion under mild conditions, with aryl iodides, bromides, triflates and chlorides. No catalyst leakage or metal contamination of the final product were observed during the HCS and SM reactions, respecting the very low limits for metal impurities in medicines established by the International Conference of Harmonization Guidelines Q3D (ICH Q3D). In addition, a deep understanding of the reaction mechanism is very important if the final target is to develop efficient protocols that can be applied at industrial level. Experimental and theoretical studies pointed out the presence of two catalytic cycles depending on the counterion, shedding light on the role of base in catalyst reduction and acetylene coordination in the HCS coupling. Finally, the development of a cross-coupling reaction to form aryldifluoronitriles in the presence of copper is discussed, highlighting the importance of inserting fluorine atoms within biological structures and the use of readily available metals such as copper as an alternative to palladium.

Au(I) Catalyzed Manipulation of Propargylic Alcohols: A New Route Towards the Synthesis of Indole Alkaloids

In this work we presented several aspects regarding the possibility to use readily available propargylic alcohols as acyclic precursors to develop new stereoselective [Au(I)]-catalyzed cascade reactions for the synthesis of highly complex indole architectures. The use of indole-based propargylic alcohols of type 1 in a stereoselective [Au(I)]-catalyzed hydroindolynation/immiun trapping reactive sequence opened access to a new class of tetracyclic indolines, dihydropyranylindolines A and furoindolines B. An enantioselective protocol was futher explored in order to synthesize this molecules with high yields and ee. The suitability of propargylic alcohols in [Au(I)]-catalyzed cascade reactions was deeply investigated by developing cascade reactions in which was possible not only to synthesize the indole core but also to achieve a second functionalization. Aniline based propargylic alcohols 2 were found to be modular acyclic precursors for the synthesis of [1,2-a] azepinoindoles C. In describing this reactivity we additionally reported experimental evidences for an unprecedented NHCAu(I)-vinyl specie which in a chemoselective fashion, led to the annulation step, synthesizing the N1-C2-connected seven membered ring. The chemical flexibility of propargylic alcohols was further explored by changing the nature of the chemical surrounding with different preinstalled N-alkyl moiety in propargylic alcohols of type 3. Particularly, in the case of a primary alcohol, [Au(I)] catalysis was found to be prominent in the synthesis of a new class of [4,3-a]-oxazinoindoles D while the use of an allylic alcohol led to the first example of [Au(I)] catalyzed synthesis and enantioselective functionalization of this class of molecules (D*). With this work we established propargylic alcohols as excellent acyclic precursor to developed new [Au(I)]-catalyzed cascade reaction and providing new catalytic synthetic tools for the stereoselective synthesis of complex indole/indoline architectures.

Sulfanyl Radical Addition to Alkynes: Revisiting an Old Reaction to Enter the Novel Realms of Green Chemistry, Bioconjugation, and Material Chemistry

In the last decade considerable attention has been devoted to the rewarding use of Green Chemistry in various synthetic processes and applications. Green Chemistry is of special interest in the synthesis of expensive pharmaceutical products, where suitable adoption of “green” reagents and conditions is highly desirable. Our project especially focused in a search for new green radical processes which might also find useful applications in the industry. In particular, we have explored the possible adoption of green solvents in radical Thiol-Ene and Thiol-Yne coupling reactions, which to date have been normally performed in “ordinary” organic solvents such as benzene and toluene, with the primary aim of applying those coupling reactions to the construction of biological substrates. We have additionally tuned adequate reaction conditions which might enable achievement of highly functionalised materials and/or complex bioconjugation via homo/heterosequence. Furthermore, we have performed suitable theoretical studies to gain useful chemical information concerning mechanistic implications of the use of green solvents in the radical Thiol-Yne coupling reactions.

Bis-Alkoxycarbonylation And Difunctionalization Of Alkenes Employing Palladium(II) Or Nickel(II) Complexes As Catalysts

Section 1 is focused on the bis-alkoxycarbonylation reaction of olefins, catalyzed by aryl α-diimine/Pd(II) complexes, for the synthesis of succinic acid ester derivatives, important compounds in many industrial fields. The opening chapter (Chapter 1) of this thesis presents an overview of the basic chemistry of organopalladium compounds and carbonylation reactions, focusing on oxidative bis-alkoxycarbonylation processes. In Chapter 2 the results obtained in the bis-alkoxycarbonylation of 1,2-disubstituted olefins are reported. The reaction proceeds under very mild reaction conditions, using an aryl α-diimine/Pd(II) catalyst and p-benzoquinone as oxidant, in the presence of a suitable alcohol. This process proved to be very efficient, selective and diastereospecific and various 2,3-disubstituted succinic esters have been obtained in high yields. In Chapter 3 the first bis-alkoxycarbonylation reaction of acrylic esters and acrylic amides, leading to the synthesis of 2-alkoxycarbonyl and 2-carbamoyl succinates respectively, is reported. Remarkably, the utilized aryl α-diimine/Pd(II) catalyst is able to promote the carbonylation of both the β- and the generally non-reactive α- positions of these alkenes. The proposed catalytic cycle is supported by DFT calculations. Section 2 is mainly focused on the Ni-catalyzed difunctionalization of unactivated alkenes tethered to unstabilized ketones. This reaction allows for a wide range of pharmaceutically useful cyclic architectures to be obtained. Chapter 4 consists of an introduction to the difunctionalization reactions of unactivated olefins. In particular, intramolecular reactions will be discussed in detail. In Chapter 5 the results obtained from the Ni-catalyzed difunctionalization of unactivated alkenes tethered to unstabilized ketones are reported. The reaction proceeds through the formation of a zinc-enolate compound, followed by a cyclization/cross-coupling reaction, which takes place in the presence of a phosphine/Ni(II) complex and an (hetero)aryl electrophile, leading to different cyclic and bicyilc architectures. In Chapter 6, preliminary results concerning the anionic cyclization of zinc enolates tethered to unactivated alkenes are presented.