Multicomponent Chemistry with Thiosulfonate and Isocyanide Building Blocks: Challenges and Opportunities for Green Chemistry
12 December 2017
Campus Middelheim, A.143 - Middelheimlaan 1 - 2020 Antwerpen (route: UAntwerpen, Campus Middelheim
Organization / co-organization:
Department of Chemistry
Bert Maes & Romano Orru
Public defence of the PhD thesis of Mr. Pieter Mampuys - Faculty of Science - Department of Chemistry
Isocyanides and thiosulfonates are versatile reagents which have seen a surge of interest over the last decades. In order to get acquainted with these building blocks, Chapter 1 provides an overview of the current synthetic strategies towards isocyanides and thiosulfonates with a strong emphasis on their green credentials, and covers also the applications of the latter in organic chemistry. This PhD dissertation further describes our efforts to employ these building blocks in various multicomponent reactions. First, Chapter 2 focuses on the synthesis of acyclic guanidines via a palladium-catalyzed oxidative coupling of isocyanides and two (different) anilines using molecular oxygen as stoichiometric oxidant. Although the target compounds can be obtained successfully, the general applicability is very limited. Chapter 3 describes a copper-catalyzed three-component reaction of amines, isocyanides and thiosulfonates which delivers isothioureas in one single step. Since isothioureas are an important precursor of guanidines, this approach is a successful alternative to the one presented in chapter 2. In addition, new applications of these isothioureas have been identified such as the preparation of challenging (hetero)arylamides, which are not (easily) accessible via classical coupling reagents. Chapter 4 provides a case study on the application of the CHEM21 Metrics Toolkit to evaluate greenness of the developed multicomponent reaction towards isothioureas and compares it with the state of the art. Moreover, the upstream processes that lead to the starting materials are also scrutinized with the aim of gaining a clearer perspective of their impact on the overall greenness of the reaction. With the isothiourea methodology in hand, Chapter 5 describes the synthesis of cyclic guanidines via in situ isothiourea formation from diamines, followed by intramolecular cyclization. In Chapter 6 is demonstrated that isocyanides and thiosulfonates, the main building blocks of this PhD dissertation, also smoothly couple into thiocarbamates under mild conditions when amines are omitted. As the solvent is actively involved to achieve high yields it can also be labeled as a three-component reaction. Chapter 7 provides a strategy for the synthesis of challenging amides via activation of amines as bench-stable thiocarbamates followed by a Grignard addition, which is complementary the one encountered in chapter 3. Finally, in Chapter 8 we go beyond thiosulfonates and disclose a novel concept for the preparation of heterocycles in which a kinetic and thermodynamic unreactive (CO2) and reactive (isocyanide) C1-reactant are successfully combined in a single transition metal-catalyzed three-component reaction.