The primary limitations of TMM cycloadditions employing diazenes are competitive MCP and dimer formation. To circumvent these problems, either very high concentrations of alkene must be used or the cycloaddition must be intramolecular. Stereoselectivity and site selectivity may also be higher in intramolecular variants of cycloadditions starting from diazenes.
Usually, unless a cyclic pi system is involved TMM cycloadditions exhibit 2π periselectivity and do not react with larger pi systems. Polar MCPs, for example, react only with the 2,3 double bond of polyunsaturated esters.
Transition-metal catalyzed reactions have the potential to quickly generate an interesting functionality. Propellanes have been generated from intramolecular cyclization under palladium catalysis.
Silylated allylic acetates may be employed for intra- or intermolecular applications. Carbonyl compounds may be used as the 2π component under the appropriate conditions. For instance, in the presence of an indium co-catalyst, the reactive 2π component of the cycloaddition below switches from the C-C to the C-O double bond.
Polarized trimethylenemethanes generated from polar MCPs are also useful substrates for (3+2) reactions with polar double bonds as the 2π component. Orthoester products are generally favored over ketene acetals.