Transition Metal-Catalyzed Isocyanide Insertions: From Noble to Base Metal Catalysis

There is no doubt that isocyanide insertion processes are highly valuable methods of generating chemical complexity. The incorporation of functionalized isocyanides provides inherently more convergent synthetic strategies towards valuable nitrogeneous products. Chapter 1 presents an updated overview of all the known isocyanide insertions catalyzed by palladium. Even though there are significant efforts being undertaken to replace palladium with cheaper and more naturally abundant metals, it is still the most widely employed metal in these types of imidoylations. Due to its unrivaled reactivity, and highly predictable chemistry, palladium catalysis is still unrivaled in the field of isocyanide insertions. This remarkable reactivity is demonstrated in Chapter 3, in which we report an imidoylative variation of the well-known Sonogashira reaction. While the basic chemistry behind an imidoylative variant of this Sonogashira transformation was already known, we utilized our expertise in the field of multicomponent cascade chemistry by following up this 3-component reaction with a conjugate cycloaddition. The result is a one-pot, two-stage transformation of o-bromoanilines 1, various functionalized isocyanides 2 and terminal alkynes 3 to directly furnish the biologically and medicinally interesting 4-aminoquinoline scaffold 4. Here, the formation of the intermediate ynimine 5 is crucial. This direct product of the imidoylative Sonogashira cross-coupling is susceptible to conjugate addition of the nucleophilic moiety already present in the aryl halide substrate. The generalization of this reactivity inspired us to include different nucleophiles, but more importantly, different electrophiles in similar cross-coupling substrates. This led to the research reported in chapter 4, where we replaced the transmetalation of the in situ formed copper acetylide with nucleophilic attack of a cyanate (Scheme 2). The resulting intermediate 8 bears significant structural resemblance to 5, but is much more electrophilic. Hence, this methodology affords the highly underinvestigated 4-aminoquinazolin-2-ones and 4-aminobenzoxazin-2-ones in moderate to good yields, in a three-component cross-coupling. Due to the increased electrophilicity of the intermediate 8 no acids are required to facilitate the cyclization. In addition to the mentioned palladium-catalyzed imidoylative cross-couplings, we were also able to utilize the much more cheaper and readily available Ni(OAc)2.4H2O as an effective catalyst in the oxidative imidoylative cross-coupling of amidinouracils 9. As described in chapter 5, we were able to devise a synthetic strategy that affords the highly underinvestigated pyrimidouracils 10 under remarkably mild conditions (i.e. base metal catalyst, recommended solvent, low temperatures, and open to air.) The oxidative imidoylation proceeds highly efficiently, affording the product 10 typically in high yield, regardless of the substituents on the substrate amidinouracil 9. The reaction also shows a high tolerance to functionalized isocyanides 2. We intended to build on the base metal-catalyzed versions of isocyanide insertions, and were curious to elaborate the cascade-type nature of chapter 3-4, so we investigated the possibility to incorporate an electrophile into the isocyanide moiety. We reported the copper(II)-catalyzed amination/ cyclization cascade of o-isocyanobenzoates 11 in chapter 6. This transformation is mechanistically significantly different from other chapters, as the catalyst most likely functions as a Lewis acid. Quinazolinones 13 were typically isolated in good yields, under relatively mild conditions. We underlined the synthetic utility by the total synthesis of several natural compounds, including rutaecarpine. The research projects highlighted in this thesis are just several examples of the high synthetic impact isocyanide insertion reactions. Especially when the isocyanide substituent can be incorporated into the final product, the benefits to the convergent nature of imidoylations cannot be ignored. However, it does require significant amounts of curiosity-driven research to develop the robust reaction conditions required to move these types of metal-catalyzed isocyanide insertions from fundamental proof of principle towards medicinally relevant syntheses.