Formation of Five- and Six-membered Heterocyclic Rings by Radical Cyclization

This brief review describes the syntheses of different five-and sixmembered heterocyclic rings in various compounds by radical cyclization.Until few years ago radicals were still a domain for mechanistically oriented research; a wealth of experimental data has led to a deeper understanding of their chemistry.Nowadays radical reactions are increasingly employed in synthesis, wherein the product is formed through reactions of radicals either with other radicals or with molecules whose electron spins are paired.In radical-radical reactions, the radicals must be continuously generated, so that an equivalent amount of radical initiator is required.The use of radical cyclization for the synthesis of heterocycles continues to grow and many new methodologies have been published in addition to the use of tributyltin hydride (Bu 3 SnH) or related triorganostannanes.The bulk of radical cyclizations in heterocyclic chemistry is still carried out by using Bu 3 SnH.The reaction conditions are generally to use an excess of Bu 3 SnH with a smaller equivalent (10-25 mol %) of a radical initiator, most commonly azobisisobutyronitrile (AIBN).The reactions are generally refluxed in benzene or toluene for 1-10 h.The purification of the product is a real problem but this problem can partially be reduced by using catalytic amount of Bu 3 SnH.Syringe pump technique for addition of tin hydride can minimize the concentration of this reagent and offer a valuable alternative when slow cyclizations are involved.This can bypass the need for large solvent volumes.In this methodology Bu 3 SnCl is reduced in situ with sodium cyanoborohydride or sodium borohydride 1-5 thereby producing small amounts of Bu 3 SnH which is continually used up generating more Bu 3 SnX (X = Br, I ) in a cycle. 6,7is process was initially developed for the reduction of alkyl halides, and it remains an excellent synthetic method for that purpose.One equivalent of Bu 3 SnH is required to reduce one equivalent of alkyl halide.Each step in the sequence is energetically favored, so side reactions are minimized.Tributyltin radical does not abstract hydrogen from the alkyl, it only attacks the halide (Br or I).Likewise, the carbon radical abstracts the hydrogen from tin much more readily than it does other C-H hydrogens.From the mechanistic point of view the process is clean and consequently results in clean reduction products.C N=N -N 2 C N . 2 + Bu 3 SnH C N + Bu 3 Sn .+ R-Br