Synthetic radical transformations

The pioneering work of Sibi and coworkers has elegantly demonstrated the use of chiral and achiral oxazohdinones in synthetic radical transformations. In the mid-1990s, Sibi and coworkers reported that LAs could facilitate very high levels of diastereoselectivity in radical allylations of bromide... 

Considering the proposed mechanism of LA-mediated isotactic control (Scheme 4), the reported synthetic radical transformations provide some usefiil insights into its potential modes of failure (Scheme 5). We reexamine these potential modes of failure while concurrendy drawing on synthetic hterature where relevant. We should clarify that our goal is not simply to highhght the factors that likely cause LA and condition dependencies but... 

The interaction between modestly strong LAs and relatively weak Lewis bases afibrds excellent stereocontrol in many synthetic radical transformations. While weak coordinative interactions may limit the effectiveness of weak LAs for isotactic control, it is unlikely to be a limiting factor in many of the LA-mediated radical polymerizations investigated to date particularly those that employ strong LAs (such as rare earth metal triflates). 

On the basis of the examples addressed thus far, it is clear that radical reactions can accomplish manifold transformations in organic synthesis. One of the outstanding achievements of synthetic radical chemistry is the development of synthetic strategies based on controlled, tandem radical cyclizations. The efficiency of such strategies is exemplified in the substantial and elegant synthetic work of D. P. Curran and his group.54 The remainder of this chapter will address the concise total syntheses of ( )-hirsutene [( )-1]55 and ( )-A9(12)-capnellene [( )-2]56 by the Curran group. 

It is important to select stoichiometric co-reductants or co-oxidants for the reversible cycle of a catalyst. A metallic co-reductant is ultimately converted to the corresponding metal salt in a higher oxidation state, which may work as a Lewis acid. Taking these interactions into account, the requisite catalytic system can be attained through multi-component interactions. Stereoselectivity should also be controlled, from synthetic points of view. The stereoselective and/or stereospecific transformations depend on the intermediary structure. The potential interaction and structural control permit efficient and selective methods in synthetic radical reactions. This chapter describes the construction of the catalytic system for one-electron reduction reactions represented by the pinacol coupling reaction. 

I didn t think that radical chemistry could be so mild and selective, is the nicer version of comments one often hears after seminars. What is the underlying reason for the misconception Probably that radical transformations often seem counterintuitive to those brought up with classical retrosynthetic schemes. As a result, the use of radicals is considered by many synthetic chemists as a last resort only to be used when other more traditional methods have failed. Additionally, radical reactions are usually regarded as being unselective and involving toxic reagents. 

Arene(tricarbonyl)chromium complexes undergo a number of synthetically important transformations not usually observed for uncomplexed arenes. The chromium tricarbonyl moiety facilitates nucleophilic, electrophilic, and radical reactions at the benzylic position. Upon complexation, one side of the aromatic ring and adjacent functionalities is blocked by the metal carbonyl moiety and highly stereoselective reactions are usually observed even at relatively remote positions. In addition, the protons of the complexed aromatic ring have a substantially higher acidity and are readily removed and further substituted by electrophiles. Finally, the aromatic ring is activated toward addition reactions using a variety of nucleophiles. 

Radical reactions provide a powerful means for manipulating the structure of organic compounds. A vast range of radical transformations is available to the synthetic organic chemist, ranging from functional group interconversions to asymmetric reactions and complex, sequential cyclization reactions where molecular complexity can be increased spectacularly in a single step. Many of these processes are complementary to more traditional polar processes and are characterized by attractive features such as the mild, neutral reaction con-... 

As the product 39 still contains the xanthate group, alternative radical transformations can be performed, which also include its removal with tris(trimethylsilyl)silane. Further manipulations of the dithiane ring comprise desulfurization or hydrolysis, thus confirming the use of such xanthates as the synthetic equivalent of a methyl and formyl radical. Two examples of the use of this chemistry for the extension of alkene-containing sugars were successfully examined, as illustrated in Scheme 27. 

The carbon-carbon bond formation via photoinduced electron transfer has recently attracted considerable attention from both synthetic and mechanistic viewpoints [240-243]. In order to achieve efficient C-C bond formation via photoinduced electron transfer, the choice of an appropriate electron donor is essential. Most importantly, the donor should be sufficiently strong to attain efficient photoinduced electron transfer. Furthermore, the bond cleavage in the donor radical cation produced in the photoinduced electron transfer should occur rapidly in competition with the fast back electron transfer. Organosilanes that have been frequently used as key reagents for many synthetically important transformations [244-247] have been reported to act as good electron donors in photoinduced electron-transfer reactions [248, 249]. The one-electron oxidation potentials of ketene silyl acetals (e.g., E°o relative to the SCE = 0.90 V for Me2C=C(OMe)OSiMe3) [248] are sufficiently low to render the efficient photoinduced electron transfer to Ceo [22], which, after the addition of ketene silyl acetals, yields the fullerene with an ester functionality (Eq. 15) [250, 251]. 

The a-aminoalkyl radicals as well as iminium ions generated as intermediates in electron-transfer reactions of amines can be used for bringing about synthetically useful transformations of amines. The synthetic applications of amine oxidation reactions brought about by thermal, electrochemical and photochemical methods as discussed below. 

Oxazolidinones have proven to be extremely useful auxiliary groups in a variety of synthetic reaction types. Thus, the Evans auxiliaries are useful in the control of configuration in enolate alkylations and concerted cycloadditions, to name a few of the more important applications. Sibi and his collaborators at North Dakota State University have pioneered the use of these auxiliary groups in radical transformations mediated by Lewis acids [21-24]. Consider the general conformational questions that arise in a carboximide, such as 12, derived from an oxazolidinone (Eq. 18). The conformer 12 is disfavored by steric factors while 13 and 14 have similar steric demands. In the absence of any chelating Lewis acid, one expects that 13 would be of lower energy than 14 because of the opposed dipoles of the anti carbonyls in this conformation. 

In the past five to ten years, significant progress has been made in designing and utilizing appropriate chiral groups to control selectivity in free-radical transformations. Specifically, amide-based chiral auxiliaries have been the most widely studied and successful of the auxiliaries. Using these auxiliaries in synthetic transformations is the topic of another chapter in this volume, and the focus here is the use of these strategies in the stereocontrolled formation of telomers and polymers. The reader is referred to Chapter 4.3 (Volume 1) for a detailed discussion of chiral auxiliaries in free-radical transformations. 

The development of tandem free-radical reactions offers synthetic chemists the opportunity to combine the one-carbon ring expansion reaction with other radical transformations such as cyclization [8a] and addition [8b] in the construction of ring-expanded bicyclics (Scheme 4). 

But before 1980, the foundations for essentially all modern synthetic radical reactions had been laid, sometimes by synthetic organic chemists but more often by physical organic chemists. Kharasch reactions (now often called atom transfer reactions) were known since the 1930s and 1940s, and tributyltin hydride was introduced in the 1960s. In the 1970s, SnAc reactions and redox chain aromatic substitutions (Minisci reactions) were already topical, and allylations with allyl-tributylstannane were first described. In short, there were a number of ways to generate and trap radicals on the one hand, and a number of fundamental transformations of radicals such as addition and cyclization to multiple bonds on the... 

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