A New Route to Three‐Dimensional Bioisosteres of Arenes: Pd‐Catalyzed Decarboxylative Cycloadditions for Efficient Construction of Bicyclo[ n .1.1]Alkane Analogues

Bicyclo[ n .1.1] systems are widely recognized as powerful bioisosteric replacements for a diverse range of substituted (hetero)aromatics. However, synthetic methods for accessing these scaffolds remain limited. Herein, we report the design and application of vinyl carbamate‐containing bridged cyclobutanes (VCBCs) as a novel modular synthon to address this challenge. In contrast to the well‐established BCB‐ and propellane‐based strain‐release synthons, our VCBC platform allows the reaction sites to extend beyond the bridgehead carbons, owing to its flexible and tunable side arm. The synthetic utility of this synthon is demonstrated through current Pd‐catalyzed decarboxylative [4 + 2] cycloaddition of VCBCs (along with their allenyl analogue) with isocyanates, which delivers a new class of urea‐containing bicyclo[3.1.1]heptane derivatives in generally high yields. These products are proposed as potential 3D bioisosteric replacements for 2‐hydroxypyrimidine (the core structural motif of pyrimidine nucleosides). Furthermore, the practical value of this protocol is underscored by a gram‐scale synthesis and diverse downstream derivatizations of the resulting products.