Intramolecular Free Radical Cyclizations

Intramolecular free radical cyclization of dicarboxylic esters leads to a-hydroxy ketones (acyloins). Reductive coupling of dicarbonyl compounds provides 1,2-diols ipinacols) and further reaction of these yields cycloalkenes (McMurry reaction). These cyclization reactions are especially valuable for the preparation of medium and large rings that are not readily accessible by other methods. 

Treatment of a,co-diesters with dispersions of sodium or a sodium-potassium alloy in refluxing toluene or xylene results in joining of the two ester moieties to furnish cyclic a-hydroxy ketones (acyloins). 

The diester is usually added to the suspension of molten, dispersed sodium in the appropriate solvent over a prolonged period, especially for the preparation of medium and large carbocyclic systems. This is to limit intermolecular coupling from competing with the desired cyclization. Since the intermediates formed during the reaction are prone to oxidation in the basic reaction medium, the cyclization should be carried out under a nitrogen atmosphere. 

In the initial step of the reductive coupling, electron transfer from Na or K to the diester leads to a di(radical anion) species (two ketyl radical anions), which then combine. Elimination of alkoxide produces the 1,2-diketone, which is further reduced to an enediolate by transfer of two electrons. Protonation of the dianion with dilute aqueous acid leads to the enediol, which tautomerizes to the a-hydroxy ketone.  

Undesirable side-reactions, such as Dieckmann ring closure and Claisen condensation reactions, often compete with the acyloin condensation. 

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Ylides (146) are cyclized by 30% aqueous hydrogen peroxide to afford the pyrido[ 1,2- ] azepines (147) (91HCA1095). The pyridof 1,2- ]azepinium system (148) is also obtainable by intramolecular free radical cyclization of 5-(l-pyridinio)-pentyl iodide (91T4077). 

X. Zhen, P. Agback, J. Plavec, A. Sandstrom, and J. Chattopadhyaya, New stereocontrolled synthesis of isomeric ( -branched [1 D-nucleosides by intramolecular free-radical cyclization— opening reactions based on temporary silicon connection, Tetrahedron 48 349 (1992). 

T. V. RajanBabu, Stereochemistry of intramolecular free-radical cyclization reactions, Acc. Chem. Res. 24 139 (1991). 

Below are shown a few examples of the types of complex structures that can be assembled by intramolecular free-radical cyclization. Note the presence of a great many polar functional groups present in the cyclization substrates which are compatible with the process. While the examples shown do not need protecting groups, a great number of other free-radical cyclizations are known which have unprotected alcohols, carbonyl groups, and carboxylic acids in the cyclization precursor. 

For an advanced discussion of intramolecular free-radical cyclizations in synthesis see M. B. Smith, Organic Synthesis, McGraw-Hill, New York, 1994, pp. 1423-1432. 

The most representative examples of intramolecular free radical cyclization in carbohydrate chemistry are the syntheses of C-branched nucleosides derivatives. The key step in C-branched nucleoside preparation is the regio- and stereo-controlled formation of a new C-C bond at the branching point of the ribofuranose ring [58]. Among published reports, a temporary silicon connection is becoming a growing interest in the syntheses of C-branched nucleosides by intramolecular radical cyclization. 

Synthesis of carbocyclic systems intramolecular free-radical cyclization, the Diels-Alder reaction, and ring-closing metathesis... 

The mechanisms of intramolecular free-radical cyclization reactions are no different from their intermolecular counterparts. The propagation part of the mechanism usually involves (1) abstraction of -Br, T, or -SeR by Bu3Sn- to give an alkyl radical, (2) one or more additions of an alkyl radical to a tt bond, and... 

In 1988, Boger and co-worker found that the intramolecular free-radical cyclization reactions of acyl radicals generated from selenol esters proceeded efficiently, suppressing competing reduction and decarbonylation (Eq. 47) [98]. 

The rings 77 are available via intramolecular free radical cyclizations catalyzed by Bu"3SnH <2005T2037>, while 78 is available in good yield via a ruthenium-catalyzed cyclisation of an enyne <2002JM09>. 

The intramolecular free radical cyclization has also been utilized for the preparation of tricyclic azetidinones [129]. 

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