Diradicals in Synthesis

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. 

Wessig P. Synthesis and modifications of amino acids and peptides via diradicals. In Renaud P, Sibi M, eds. Radicals in Organic Synthesis. Wiley, 2001. 

Likewise, benzyldihydroisoquinolinium derivatives can be used in a photochemical synthesis of tetrahydroisoquinolines. Thus, 2-(2-trimethyl-silylmethylphenylmethyl)-3,4-dihydroisoquinoliniun perchlorates have been successfully cyclized, as in the synthesis of the protoberbine alkaloids (+)xylopinine and (+)stylopine. The reaction proceeds via SET from the xylyl donor to the iminium moiety, fragmentation of the benzylsilane radical cation and carbon-carbon bond formation in the intermediate diradical. The synthesis is rather general and the yields compare favorably with those obtained from related substrates via a dipolar cycloaddition methodology [298] (Sch. 27). 

Trimethylene)bis(2,6-di-t-butylphenoxy) diradical 1018 Trimethylolphenol 627 Trimethylsilyloxydienes, in synthesis of phenols 441-443... 

Herrera et al. [97,98] have reported the usage of Norrish-Yang photocyclization for the synthesis of new spirocyclic monosaccharide derivatives of types 243 and 244 via a hydrogen atom transfer (HAT) reaction promoted by a 1,2-diketone 241, in its excited state, followed by C-C tetrasubstituted bond formation in a diastereo-selective manner (Fig. 8.59). Of special interest is the study of the tendency to inversion at C5 (for examples of epimerization of anomeric and pseudoanomeric radicals, see [99, 100]), probably triggered by conformational changes that the 1,4-diradical intermediate 242 undergoes in its triplet state, within its lifetime (for discussions of the lifetime of diradicals in solution, see [101, 102]) before the intersystem crossing (ISC) occurs. 

DNA cleavage (mimic of esperamicin) [89]. The related diradical mechanism was operated in the photoannulation reaction of 2-aryl-3-isopropoxy-l,4-naphthoquinone available from 5 (R = i-Pr) and was fruitful in synthesis of dimethylnaphthogeranine E [90]. 

Photochemical synthesis of sulphoxides was reported for the first time by Foote and Peters111 in 1971. They found that dialkyl sulphides undergo smoothly dye-photosensitized oxidation to give sulphoxides (equation 32). This oxidation reaction has been postulated to proceed through an intermediate adduct 63, which could be a zwitterionic peroxide, a diradical or cyclic peroxide, which then reacts with a second molecule of sulphide to give the sulphoxide (equation 33). 

The anticancer activity of complex natural products having a cyclodecenediyne system [for a review see <96MI93>] has prompted the synthesis of 54 (X = CH2 and OCH2) <96CC749> and 55 (R = a-OH and p-OH) <95AG(E)2393> on the basis that such compounds are expected to develop anticancer activity as the P-lactam ring opens. This is because cycloaromatization can only occur in the monocyclic enediyne and the diradical intermediate in the cyclization is thought to be the cytotoxic species. 

Photocycloaddition of Alkenes and Dienes. Photochemical cycloadditions provide a method that is often complementary to thermal cycloadditions with regard to the types of compounds that can be prepared. The theoretical basis for this complementary relationship between thermal and photochemical modes of reaction lies in orbital symmetry relationships, as discussed in Chapter 10 of Part A. The reaction types permitted by photochemical excitation that are particularly useful for synthesis are [2 + 2] additions between two carbon-carbon double bonds and [2+2] additions of alkenes and carbonyl groups to form oxetanes. Photochemical cycloadditions are often not concerted processes because in many cases the reactive excited state is a triplet. The initial adduct is a triplet 1,4-diradical that must undergo spin inversion before product formation is complete. Stereospecificity is lost if the intermediate 1,4-diradical undergoes bond rotation faster than ring closure. 

These results can be interpreted in terms of competition between recombination of the diradical intermediate and conformational equilibration, which would destroy the stereochemical relationships present in the azo compound. The main synthetic application of azo compound decomposition is in the synthesis of cyclopropanes and other strained-ring systems. Some of the required azo compounds can be made by 1,3-dipolar cycloadditions of diazo compounds (see Section 6.2). 

The group ofWalborsky probably has described one of the first true anionic/radi-cal domino process in their synthesis of the spirocyclopropyl ether 2-733 starting from the tertiary allylic bromide 2-730 (Scheme 2.161) [369]. The first step is a Michael addition with methoxide which led to the malonate anion 2-731. It follows a displacement of the tertiary bromide and a subsequent ring closure which is thought to involve a SET from the anionic center to the carbon-bromine anti bonding orbital to produce the diradical 2-732 and a bromide anion. An obvious alternative Sn2 halide displacement was excluded due to steric reasons and the ease with which the reaction proceeded. 

The cleavage of the intermediate 1,4-diradical can also become the major path as in the synthesis of methylenecyclopentane (4.8) 408). 

Mechanistic evidence indicates 450,451> that the triplet enone first approaches the olefinic partner to form an exciplex. The next step consists in the formation of one of the new C—C bonds to give a 1,4-diradical, which is now the immediate precursor of the cyclobutane. Both exciplex and 1,4-diradical can decay resp. disproportionate to afford ground state enone and alkene. Eventually oxetane formation, i.e. addition of the carbonyl group of the enone to an olefin is also observed452. Although at first view the photocycloaddition of an enone to an alkene would be expected to afford a variety of structurally related products, the knowledge of the influence of substituents on the stereochemical outcome of the reaction allows the selective synthesis of the desired annelation product in inter-molecular reactions 453,454a b). As for intramolecular reactions, the substituent effects are made up by structural limitations 449). 

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