New Methods in Alkylidenecarbene Chemistry: A Mild Route to Cycloalkynes

While the strain-accelerated cycloaddition of cyclooctynes has played a central role in the development of biomolecule conjugation and a range of related technologies, the preparation of these highly reactive alkynes remains challenging. In this context, we report an efficient, two-step method for the synthesis of cyclooctynes from cycloheptanones by way of 5-hydroxyalkyl-1H-tetrazoles. Treatment of these substrates with carbodiimide reagents leads to the formation and 1,2-rearrangement of a putative alkylidenecarbene intermediate generating the desired products in good to excellent yield. This ring expansion strategy displays broad substrate scope and functional group tolerance and is performed under mild, non-basic conditions. Details of this methodology and its application to the synthesis of a range of cyclooctynes, both stable and transient will be described.