Digital archive of theses discussed at the University of Pisa


Tesi etd-10022020-154720

Thesis type
Tesi di laurea magistrale
Thesis title
Synthesis of (Hetero)biaryls Through the Use of Diazonium Salts
Course of study
relatore Prof. Bellina, Fabio
  • synthesis
  • (hetero)biaryls
  • diazonium salts
Graduation session start date
Release date
The (hetero)biaryl structural motif, which is frequently found in natural products and commercially available agrochemicals and pharmaceuticals, exhibits significant bioactivities across a wide range of therapeutic classes, including antihypertensive, antifungal, antitumor, antirheumatic, and anti-inflammatory agents. Additionally, the (hetero)biaryl scaffold is a predominant feature in several functional organic materials such as liquid crystals for LCD screens, organic light-emitting diodes (OLEDs), organic photovoltaics and organic field effect transistor. For this reason, reactions able to join two (hetero)aromatic rings to form unsymmetrical (hetero)biaryls through the formation of a new σ Csp2-Csp2 bond are among the most widely used processes in the pharmaceutical, agrochemical and electronic industry and beyond. As a result, for over a century, organic chemists have sought to develop new and more efficient (hetero)aryl-(hetero)aryl bond-forming methods.
In this context arenediazonium salts, since their discovery in 1858 by Peter Griess, have emerged as excellent reagents thanks to their highly versatile nature in organic synthesis, that comes from the unique properties of the diazonium linkage. In fact, their reactivity is expressed through a dinitrogen loss by heterolytic or homolytic dissociation into an aryl carbocation or aryl radical respectively, thus displaying large spectrum of reactivities that span from free-radical to organometallic chemistry. Furthermore, arenediazonium salts attracted and keep attract chemist because they combine several advantages as starting materials in organic synthesis: 1) they are easily prepared in large quantities from corresponding commercially available anilines; 2) their reactions take place at mild conditions; 3) the coupling reactions can proceed with high chemo- and regioselectivity; 4) the leaving group N2 does not interfere with the reaction mixture.
The rich legacy of arenediazonium salts in the synthesis of (hetero)biaryls, built around the seminal works of Pschorr, Gomberg and Bachmann more than a century ago, continues to make important contributions at the various evolutionary stages of modern (hetero)biaryl synthesis. Thus, based on in-depth mechanistic analysis and design of novel pathways and reaction conditions, arenediazonium salts have been successfully employed in almost all type of transformation, from organometallic reactions such as Suzuki-Miyaura coupling, Stille coupling, Negishi coupling and Hiyama coupling through applications of transition metal/photoredox catalyst, to transition-metal free thermal, photochemical, and electrochemical radical chain reactions. In this way, the scope and ease of (hetero)biaryl synthesis with arenediazonium salts has enormously expanded and improved over the years through several researches, studies and efforts carried out by chemists all over the world. Recent developments have indeed provided a facile synthetic access to a wide variety of unsymmetrical (hetero)biaryl compounds of pharmaceutical, agrochemical, and optoelectronic importance with green scale-up options, and created opportunities for late-stage modification of important biological molecules such as peptides and nucleosides. Hence, regardless of the long history, arenediazonium salts still attract attention, and new developments have been emerging constantly.
This thesis consists of two parts: a desk-based and an experimental one. In the desk-based part, the aim is to collect and summarize all the protocols reported in literature to date for the synthesis of (hetero)biaryl compounds involving aryldiazonium salts, highlighting the advantages and disadvantages of each procedure and reporting the possible applications in the industrial field.
About the experimental part (interrupted by CoVid-19 pandemic), in literature there are very few reports regarding the direct and selective C−H direct arylation of azoles with aryldiazonium salts. In particular, in this context there are no studies about the arylation of imidazoles and their derivatives (1-methyl-1H-imidazole, 1,2-dimethyl-1H-imidazole, 1-methyl-1H-benzo[d]-imidazole, etc.). Therefore, intrigued by this unexplored field, and in view of the fact that azoles are ubiquitous features of biologically active natural products, pharmaceuticals and fluorescent dyes and synthetic protocols that enable the direct and selective elaboration of these heteroaromatics are invaluable tools for natural product synthesis and medicinal chemistry, I decided to develop new protocols for the selective and direct C−H arylation of imidazoles (and other azoles) with arenediazonium salts. Since I won the “Erasmus+ Traineeship” scholarship, the experimental part is formed by a study realized at the university of Pisa with prof. Fabio Bellina and one carried out at the university of Göttingen (Germany) under the supervision of prof. Lutz Ackermann.
Regarding the first study, the goal was to develop the direct C−H arylation of imidazoles (and other azoles) with aryldiazonium salts in transition-metal free conditions. Through a preliminary study, I developed a (unfinished) catalyst-free procedure for the selective C−H arylation of 1,2-dimethyl-1H-imidazole, 1H-benzo[d]imidazole, 1-methyl-1H-benzo[d]-imidazole and 1H-pyrazole with electron-poor arenediazonium salts in mild conditions with moderate yields (5 examples, 28-58% yield).
About the second study, the goal was to develop new protocols for the selective photoredox C−H arylation of imidazoles (and other heteroarenes) with arenediazonium salts through the use of manganese-based photocatalysts. However, unfortunately this study did not furnish the expected results due to its premature termination due to Covid-19 pandemia.