Four-Component Reactions of [n.1.1]Propellanes (n = 1 or 3) Triggered by Electrophilic Activation

Exposure of [n.1.1]propellanes (n = 1 or 3) to acidic nucleophiles typically gives decomposition products due to the instability of bicyclo[n.1.1]alkyl carbocations. This instability makes the synthesis of functionalized bicyclo[n.1.1]alkanes from protic nucleophiles by electrophilic activation of [n.1.1]propellanes particularly challenging. In stark contrast, we now report a four-component reaction between [n.1.1]propellanes (n = 1 or 3), N-iodosuccinimide, nine cyclic ethers and ten classes of protic nucleophiles, that maintains the structural integrity of the bicyclo[n.1.1]alkyl motif in the products. Crucially, this reaction gives one-step access to 4-hydroxy thalidomide derivatives that enabled us to demonstrate in a whole cell assay that a n-butoxy-bicyclo[1.1.1]pentyl linker is tolerated by cereblon, a component of E3 ligase, which is an important target of proteolysis-targeting chimeras. Experimental rate law and theoretical calculations with a model nucleophile suggest that the four-component reaction relies on the attack by THF of a halogen bond complex formed between N-iodosuccinimide and the propellane, which is assisted by hydrogen bonding of the protic nucleophiles to the succinimide component.