Radical cyclization reactions are organic chemical transformations that yield cyclic products through radical intermediates. They usually proceed in three basic steps: selective radical generation, radical cyclization, and conversion of the cyclized radical to product.
Introduction 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:
A method must be available to generate a radical selectively on the substrate. Radical cyclization must be faster than trapping of the initially formed radical. All steps must be faster than undesired side reactions such as radical recombination or reaction with solvent. Advantages: because radical intermediates are not charged species, reaction conditions are often mild and functional group tolerance is high and orthogonal to that of many polar processes. Reactions can be carried out in a variety of solvents (including arenes, alcohols, and water), as long as the solvent does not have a weak bond that can undergo abstraction, 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).
Mechanism and stereochemistry
Prevailing mechanism 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).
(1) Substituents that affect the stability of these transition states can have a profound effect on the site selectivity of the reaction. Carbonyl substituents at the 2-position, for instance, encourage 6-endo ring closure. Alkyl substituents at positions 2, 3, 4, or 6 enhance selectivity for 5-exo closure. Cyclization of the homologous 6-heptenyl radical is still selective, but is much slower—as a result, competitive side reactions are an important problem when these intermediates are involved. Additionally, 1,5-shifts can yield stabilized allylic radicals at comparable rates in these systems. In 6-hexenyl radical substrates, polarization of the reactive double bond with electron-withdrawing functional groups is often necessary to achieve high yields. Stabilizing the initially formed radical with electron-withdrawing groups provides access to more stable 6-endo cyclization products preferentially.
(2) Cyclization reactions of vinyl, aryl, and acyl radicals are also known. Under conditions of kinetic control, 5-exo cyclization takes place preferentially. However, low concentrations of a radical scavenger establish thermodynamic control and provide access to 6-endo products—not via 6-endo cyclization, but by 5-exo cyclization followed by 3-exo closure and subsequent fragmentation (Dowd-Beckwith rearrangement). Whereas at high concentrations of the exo product is rapidly trapped preventing subsequent rearrangement to the endo product Aryl radicals exhibit similar reactivity.
(3) Cyclization can involve heteroatom-containing multiple bonds such as nitriles, oximes, and carbonyls. Attack at the carbon atom of the multiple bond is almost always observed. In the latter case attack is reversible; however alkoxy radicals can be trapped using a stannane trapping agent.
Stereoselectivity The diastereoselectivity of radical cyclizations is often high. In most all-carbon cases, selectivity can be rationalized according to Beckwith's guidelines, which invoke the reactant-like, exo transition state shown above. Placing substituents in pseudoequatorial positions in the transition state leads to cis products from simple secondary radicals. Introducing polar substituents can favor trans products due to steric or electronic repulsion between the polar groups. In more complex systems, the development of transition state models requires consideration of factors such as allylic strain and boat-like transition states
(4) Chiral auxiliaries have been used in enantioselective radical cyclizations with limited success. Small energy differences between early transition states constitute a profound barrier to success in this arena. In the example shown, diastereoselectivity (for both configurations of the left-hand stereocenter) is low and enantioselectivity is only moderate.
(5) Substrates with stereocenters between the radical and multiple bond are often highly stereoselective. Radical cyclizations to form polycyclic products often take advantage of this property.
Scope and limitations
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