Acceleration of 1,3-Dipolar Cycloadditions by Integration of Strain and Electronic Tuning

The
1,3-dipolar cycloaddition between azides and alkynes provides
new means to probe and control biological processes. A major challenge
is to achieve high reaction rates with stable reagents. The optimization
of alkynyl reagents has relied on two strategies: increasing strain
and tuning electronics. We report on the integration of these strategies.
A computational analysis suggested that a CH → N aryl substitution
in dibenzocyclooctyne (DIBO) could be beneficial. In transition states,
the nitrogen of 2-azabenzo-benzocyclooctyne (ABC) engages in an n→π*
interaction with the C=O of α-azidoacetamides and forms a hydrogen
bond with the N–H of α-diazoacetamides. These dipole-specific
interactions act cooperatively with electronic activation of the strained
π-bond to increase reactivity. We found that ABC does indeed
react more quickly with α-azidoacetamides and α-diazoacetamides
than its constitutional isomer, dibenzoazacyclooctyne (DIBAC). ABC
and DIBAC have comparable chemical stability in a biomimetic solution.
Both ABC and DIBO are accessible in three steps by the alkylidene
carbene-mediated ring expansion of commercial cycloheptanones. Our
findings enhance the accessibility and utility of 1,3-dipolar cycloadditions
and encourage further innovation.