Unusual Cyclizations

Abstract

Although many radical cyclizations play prominent roles in organic synthesis and an ever increasing body of fundamental information aids in the constant development of new radical processes, a number of cyclization modes remain underrepresented. Such “unusual” gaps in the arsenal of available transformations exist for a variety of ring sizes. For example, even fast and stereoelectronically favorable 3‐exo and 4‐exo cyclizations are often rendered impossible by the high thermodynamic cost for the formation of strained small cycles. In contrast, 5‐endo cyclizations are exothermic but disfavored stereoelectronically and often slow. Moreover, even the most common five‐ or six‐membered rings are often made via an unusual class of cycloaromatization reactions where radical formation from a nonradical precursor is coupled with the cyclization step. A new set of problems appears for the formation of larger rings where the cyclizations are disfavored entropically. Additionally, certain factors disfavor even the well‐represented cyclization topologies, independent on the ring size. In particular, most cyclic closures involve carbon‐carbon bond formation via carbon radical addition to an alkene or alkyne, whereas radical ring closure via the formation of C‐heteroatom bonds are relatively scarce. We expand our discussion to radical cyclizations that proceed via CO and CN bond formation, which often provide an efficient approach to the construction of heterocycles. In our discussion, we highlight a number of factors that are useful for promoting unusual cyclizations: destabilization of reactants, stabilization of the cyclic products, electronic and conformational effects on the transition states, as well as coupling of thermodynamically unfavorable events with highly exothermic follow‐up steps.

Rules for Anionic and Radical Ring Closure of Alkynes

“…Instead, the cyclic products of such exo-cyclizations are expected to undergo a fast ring opening similar to the ring opening of cyclopropylmethyl radicals, commonly referred to as “radical clock” . However, the significant decrease in endothermicity for the cyclization of the Ph-substituted alkyne suggests that, with a proper effort, it may be possible to shift the equilibrium in favor of the cyclic form and to design efficient 3-exo-dig radical cyclizations, as has been accomplished for the respective trigonal closures …”

5-Endo Cyclizations of NHC-Boraallyl Radicals Bearing Ester Substituents: Characterization of Derived 1,2-Oxaborole Radicals and Boralactones

“…The formation of 5 was unexpected because 5- endo radical cyclizations are disfavored and examples are sparse . Moreover, radical cyclizations onto the O atoms of carbonyl groups are even more unusual .…”

SnAP-eX Reagents for the Synthesis of Exocyclic 3-Amino- and 3-Alkoxypyrrolidines and Piperidines from Aldehydes

“…Electron-rich aromatic and heteroaromatic or bulky aldehydes/ketones afforded higher amounts of protodestannylated side products ( 7d , 7e , 8d , 8e ), but some amounts of the desired products could be isolated. The formation of these products requires a disfavored 5- endo - trig cyclization, which may be responsible for the lower isolated yields than those observed for the piperidine formations. In some cases (i.e., 7d ), we found the use of alternative copper sources provided a small boost in isolated yield, suggesting that further substrate specific optimization will be possible.…”