Radical cyclization

Radical cyclization reactions are organic chemical transformations that yield cyclic products via radical intermediates. They usually proceed in three basic steps: selective radical generation, radical cyclization, and conversion of the cyclized radical to product.

Radical cyclization reactions produce mono- or polycyclic products through the action of radical intermediates. Because they are intramolecular transformations, they are often very rapid and selective. Selective radical generation can be achieved at carbons bound to a variety of functional groups, and reagents used to effect radical generation are numerous. The radical cyclization step usually involves the attack of a radical on a multiple bond. After this step occurs, the resulting cyclized radicals are quenched through the action of a radical scavenger, a fragmentation process, or an electron-transfer reaction. Five- and six-membered rings are the most common products; formation of smaller and larger rings is rarely observed.

Three conditions must be met for an efficient radical cyclization to take place:

Advantages: because radical intermediates are not charged species, reaction conditions are often mild and functional group tolerance is high. Reactions can be carried out in nearly any solvent, and products are often synthetically useful compounds that can be carried on using existing functionality or groups introduced during radical trapping.

Disadvantages: the relative rates of the various stages of radical cyclization reactions (and any side reactions) must be carefully controlled so that cyclization and trapping of the cyclized radical is favored. Side reactions are sometimes a problem, and cyclization is especially slow for small and large rings (although macrocyclizations, which resemble intermolecular radical reactions, are often high yielding).

Because many reagents exist for radical generation and trapping, establishing a single prevailing mechanism is not possible. However, once a radical is generated, it can react with multiple bonds in an intramolecular fashion to yield cyclized radical intermediates. The two ends of the multiple bond constitute two possible sites of reaction. If the radical in the resulting intermediate ends up outside of the ring, the attack is termed "exo"; if it ends up inside the newly formed ring, the attack is called "endo." In many cases, exo cyclization is favored over endo cyclization (macrocyclizations constitute the major exception to this rule). 5-hexenyl radicals are the most synthetically useful intermediates for radical cyclizations, because cyclization is extremely rapid and exo selective. Although the exo radical is less thermodynamically stable than the endo radical, the more rapid exo cyclization is rationalized by better orbital overlap in the chair-like exo transition state (see below).

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