Towards New Linchpin Reagents for the Direct Preparation of NCO-Containing Molecules

Abstract

The development and application of reagents that serve as building blocks for the construction of molecules have resulted in significant advances to the scientific community. Among these, linchpins are small, strategically designed molecules that can be chemoselectively functionalized by sequential reactions, enabling the coupling of two or more reagents through a single, central scaffold. While there is literature precedent for olefin, ketone, and polyene-forming linchpins, no such linchpin exists for amide synthesis despite the ubiquitous nature of these and other NCO-containing subunits in pharmaceuticals and agrochemicals. This thesis focuses on the development of new linchpin reagents for NCO-containing products through the formation of C-N and C-X bonds. Isocyanates are useful synthons and reactive intermediates. To control the exposure to these toxic reagents and their instability, blocked (or masked) isocyanates have been developed: an equilibrium generates the isocyanate in-situ, allowing for safer precursors and better control over the concentration of the reactive isocyanate. This strategy enables the development of new reactivity, particularly for heteroatom-substituted isocyanates. In Chapter 2, a bench-stable masked O-isocyanate with optimized leaving groups (OPh and OBz) is proven to indeed be an amide linchpin reagent, overcoming the limitations of traditional amide synthesis with a built-in N-C(=O) bond. The C(=O)-OPh and N-OBz bonds can undergo sequential reactions to functionalize the N-C=O subunit. The biselectrophilicity of the linchpin reagent imparts unique reactivity, making them attractive as linchpin molecules with high chemoselectivity. The linchpin reagent was first functionalized via rhodium-catalyzed electrophilic amination, followed by derivatization using Grignard reagents to provide hindered secondary amides and enamides. While this method was limited by its incompatibility with alkyl boronic acids, it provided a novel and effective route to amide derivatives. Tertiary amides were also accessed by trapping of the magnesium amidate intermediate with an alkylating agent. Finally, extensions toward a general NCO linchpin were explored through the synthesis of lactams and unsymmetrical ureas. In Chapter 3, a simpler, amphoteric linchpin is developed to overcome the limitations of the linchpin developed in Chapter 2. The simpler linchpin reagent was first functionalized via reductive amination, followed by derivatization with Grignard reagents to provide secondary amides or with amines to provide unsymmetrical ureas. While this method does give access to N-alkyl amides, it does not yet extend to ureas due to competing reaction pathways. In summary, these studies show that linchpin-based methods can simplify the synthesis of NCO-containing molecules, offering chemists new tools for assembling complex structures with importance in agrochemical and pharmaceutical industries.