Intramolecular 3+21 cycloaddition radical reactions

Unexpectedly, a completely different reaction took place in the oxidation of 2-(l-propenyl)phenol (111) with PdCh. Carpanone (112) was obtained in one step in 62% crude yield. This remarkable reaction is explained by the formation of o-quinone, followed by the radical coupling of the side-chain. Then the intramolecular cycloaddition takes place to form carpanone[131]. 

One of the very rare examples of a combination of a radical with a pericydic reaction - in this case a [4+2] Diels-Alder cycloaddition - is depicted in Scheme 3.83 [133]. The sequence, elaborated by Malacria and coworkers, is based on the premise that the vinyl radical 3-341 formed from the substrate 3-340 using tributyltin hydride exists mainly in the Z -form. This is reduced by a hydrogen atom to form a 1,3-diene, which can undergo an intramolecular Diels-Alder reaction via an exotransition state reaction (the chain lies away from diene). 

Another complication that can arise in these reactions is that a cycloaddition reaction of the radical intermediate formed in the tin hydride reduction, to an adjacent carbon-carbon double bond, can compete with the simple reduction reaction. This occurs when a five- or six-membered ring can be formed in an intramolecular cycloaddition reaction. For example, Beckwith and Lawrence96 found both five- and six-membered rings in the product when l-bromo-2,2,5-trimethylhex-l-ene was treated with tributyltin hydride (Scheme 15). 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

A radical-cation initiated intramolecular cycloaddition of 3 to 4 has been reported to occur using tris(4-bromophenyl)amminium hexachloroantimonate (TBAH).22 A number of Bronsted acids including trifluoroacetic acid can also effect this reaction. 

This chapter begins with an introduction to the basic principles that are required to apply radical reactions in synthesis, with references to more detailed treatments. After a discussion of the effect of substituents on the rates of radical addition reactions, a new method to notate radical reactions in retrosynthetic analysis will be introduced. A summary of synthetically useful radical addition reactions will then follow. Emphasis will be placed on how the selection of an available method, either chain or non-chain, may affect the outcome of an addition reaction. The addition reactions of carbon radicals to multiple bonds and aromatic rings will be the major focus of the presentation, with a shorter section on the addition reactions of heteroatom-centered radicals. Intramolecular addition reactions, that is radical cyclizations, will be covered in the following chapter with a similar organizational pattern. This second chapter will also cover the use of sequential radical reactions. Reactions of diradicals (and related reactive intermediates) will not be discussed in either chapter. Photochemical [2 + 2] cycloadditions are covered in Volume 5, Chapter 3.1 and diyl cycloadditions are covered in Volume 5, Chapter 3.1. Related functional group transformations of radicals (that do not involve ir-bond additions) are treated in Volume 8, Chapter 4.2. 

The third radical cation structure type for hexadiene systems is formed by radical cation addition without fragmentation. Two hexadiene derivatives were mentioned earlier in this review, allylcyclopropene (Sect. 4.4) [245] and dicyclopropenyl (Sect. 5.3) [369], The products formed upon electron transfer from either substrate can be rationalized via an intramolecular cycloaddition reaction which is arrested after the first step (e.g. -> 133). Recent ESR observations on the parent hexadiene system indicated the formation of a cyclohexane-1,4-diyl radical cation (141). The spectrum shows six nuclei with identical couplings of 11.9G, assigned to four axial p- and two a-protons (Fig. 29) [397-399]. The free electron spin is shared between two carbons, which may explain the blue color of the sample ( charge resonance). At temperatures above 90 K, cyclohexane-1,4-diyl radical cation is converted to that of cyclohexene thus, the ESR results do not support a radical cation Cope rearrangement. 

Heating the diselenoallene 140 leads to an intramolecular cycloaddition affording the fused selenin 141 (Scheme 15) <2001JOG1787>. The reaction appears to take place by an initial intramolecular hydrogen abstraction by the sp-hybridized carbon of the allene affording a diradical intermediate. Radical coupling then leads to the selenin. The cyclic allene precursor could be prepared by dilithiation of the benzylacetylene followed by treatment of the bis-selenocyanate. 

The presence of a quaternary carbon atom is frequently encountered in sesquiterpene natural products and it often creates a synthetic challenge when two or more quaternary carbon atoms are present contiguously. The synthetic strategies for the construction of quaternary carbon centers involve sigmatropic rearrangements/ intramolecular cycloaddition/ and the reaction of tertiary carbon nucleophiles with a carbon electrophile. Recently, radical cyclization strategies turned out to be very effective for this purpose. For example, Srikrishna utilized the radical cyclization reaction to prepare tricyclo[6.2.1.0 - ]undecane system, which is present in several sesquiterpenes such as zizaenes and prelacinanes, and Chen demonstrated that a tandem radical cyclization approach is an efficient method for constructing the two quaternary carbon centers in the cedrene skeleton. ... 

Allyliminium compounds such as [170] undergo intramolecular cycloaddition reactions (51) in protic solvents. (Stavinoha et al., 1981). The fact that when methanol is used as solvent the products contain a methoxyl group is good evidence for the reactions occurring via radical ions. Irradiation of... 

In conclusion, C-C bond formation on carbohydrates has absorbed lots of widely used methods from general synthetic organic chemistry. Typical among these methods are intramolecular alkylation and intramolecular condensation of aldehyde with enolates, phosphonates, and nitro-stabilized anions. Metal-mediated radical reactions, cycloadditions, and rearrangements have also been applied frequently. 

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