The Isocyanide Strikes Back
Authors:   , Roose Thomas Ruben 
Published: August 2024

The tunable reactivity of the isocyanides by transition metals has evolved into numerous useful applications of this C1 building block, such as the Pd-catalyzed imidoylative cross-coupling reactions. In addition to Pd, the 1st row transition metals are increasingly used in imidoylation reactions as more benign and chemically divers alternative catalysts. Although mechanistic studies are still scarce, distinct proposed catalytic cycles in the literature are discussed and categorized according to (I) the (hetero)atom bound to, and (II) the type of bonding, with the transition metal (σ- or π- bond), in which the (formal) insertion occurs. Within the imidoylative transformations (formal) insertion into a TM-C/N σ -bond is rather established, however, insertion into a TM-C/N π-bond, or imidoylative group transfer reaction, remains less explored. In particular, transition metal-catalyzed carbene transfer to isocyanides, which provide chemically versatile and reactive heteroallenes (i.e. ketenimines). In chapter 1, the vibrancy and richness of isocyanide chemistry within transition metal catalysis are demonstrated. While Type I-A and I-B isocyanide insertion processes (Section 1.2) have seen significant development over the past decade, Type II isocyanide insertion (Scheme 6A, Section 1.3), particularly involving carbene transfer, is still in its early stages. The difference is evident not only mechanistically, but also in the number of reported base metal-catalyzed transformations. Despite this, both fields are stille largely dominated by noble metal-catalyzed processes. The remainder of this thesis will specifically focus on Type- II isocyanide insertion, emphasizing carbene transfer.
In chapter 2, the discussion centers on the first iron-catalyzed carbene transfer to isocyanides, followed by the in situ transformation of the ketenimine intermediate. The catalyst, the ferrate complex [Fe(CO)3NO]Bu4N (Hieber anion), efficiently catalyzes carbene transfer using α-diazo ester as the carbene precursor. The resulting ketenimine can be trapped in situ by various bis-nucleophiles, yielding a diverse array of heterocycles. Notably, the transformation exhibits high tolerance for different types of isocyanides, including more functionalized ones like tryptamine-derived isocyanides.
The use of the Hieber anion in the dearomative spirocyclization of tryptamine-derived isocyanides will be discussed in Chapter 3. The use of the iron-based catalyst in the carbene transfer/dearomative spirocyclization cascade results in the formation of spiroindolenines in good yields. Although the scope of α-diazo esters as carbene precursors is somewhat limited, careful modification of the indole moiety of the isocyanide enables the application of this methodology as a key step in the formal total synthesis of several monoterpenoid indole alkaloids.
In chapter 4, the exploration of alternative carbene precursors for carbene transfer to isocyanides is presented, aiming to avoid the use of hazardous diazo compounds. Given the instability and potential explosiveness of diazo derivatives lacking an electron-withdrawing group, Zn-carbenoids are introduced as a novel carbene precursor. These Zn-carbenoids, derived from α-acyloxy halides, are, in turn, derived from the corresponding aldehyde. Rhodium is identified as the optimal catalyst for carbene transfer using Zn-carbenoids derived from α-acyloxy halides, following extensive screening of various (base) metal sources.
Chapter 5 outlines future directions in the field of transition metal-catalyzed group transfer reactions to isocyanides, building on the research presented. Additionally, this chapter explores curiosity-driven projects related to the design and use of highly functionalized isocyanides. Overall, the concepts presented encompass projects that are either unfinished or based on conceptual ideas.