Radical reactions in the synthesis

Free-radical reactions in the synthesis of diketopiperazines and other cyclic derivatives of a-aminoacids 97CRV53. 

Scheme 3.57. Domino radical reaction in the synthesis of benzothienoquinoline derivatives.

Hopefully this book will meet the challenge of convincing a large number of scientists of the benefits of radical chemistry and spark novel developments in the fields of new radical methodology and the application of radical reactions in the synthesis of complex molecules. 

Scheme 3.73. Samarium(M) iodide-promoted domino radical reaction in the synthesis ot paeonilactone B (3-289).

In this chapter, the main focus will be on two types of reactions deahng with both the creation of carbon-carbon bonds on amino acids and peptides and carbon-carbon bond fragmentations, all of which proceed via radical intermediates. Much of the earlier work on the use of free radical reactions in the synthesis of a-amino acids and derivatives has been pubhshed in an extensive review in 1997 by Easton [1]. 

For mechanistic discussions and many early examples of radical reactions in the synthesis of oxacyclic and other natural products, see C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237. 

The use of free-radical reactions in organic synthesis started with the reduction of functional groups. The purpose of this chapter is to give an overview of the relevance of silanes as efficient and effective sources for facile hydrogen atom transfer by radical chain processes. A number of reviews [1-7] have described some specific areas in detail. Reaction (4.1) represents the reduction of a functional group by silicon hydride which, in order to be a radical chain process, has to be associated with initiation, propagation and termination steps of the radical species. Scheme 4.1 illustrates the insertion of Reaction (4.1) in a radical chain process. 

The Hunsdiecker reaction is a free-radical reaction for the synthesis of an alkyl halide. The starting material comes from the reaction of a silver carboxylate with a solution of a halogen in a solvent such as carbon tetrachloride (see Figure 12-44). The overall free-radical mechanism is shown in Figure 12-45. 

Pattenden and coworkers have designed and performed a cascade of radical reactions towards the synthesis of angular triquinanes72. Irradiation of the refluxed benzene solution containing a 1 1 mixture of diastereomers of bromide 7 and (TMS SiH gave the corresponding triquinane oxime 8 as a 1 1 mixture of a- and /J-methyl diastereomers in 38% yield. 

Chapter 4 by J.J. Li reviews radical cyclization reactions in the total synthesis of indole alkaloids. The use of free radical chemistry in the synthesis of alkaloids has grown markedly because of the mild reaction conditions, tolerance of a wide variety of functional groups, and the good stereoselectivities. 

The recent applications of photochemical reactions to carbohydrates are in accordance with the great development of radical reactions in organic synthesis this last decade. 

This reaction, reported in 1960, has been shown not only to be one of the most useful photochemical processes for selective functionalization of an unactivated carbon atom in organic synthesis, but has also led to general recognition of the utility of photochemical and radical reactions in organic synthesis. 

Schemes 5 and 6 outline the functionalization of a 10/1-Me by a steroidal 6/f-ol [1] and a 2/3-61 nitrite [6], Functionalization of 13/i-Me by a 20a-ol nitrite [7] and functionalization in the terpenoid field [8] are outlined in Schemes 7 and 8. The last example involves a 7-membered cyclic transition state that seldom occurs. Scheme 9 outlines a recent application of the Barton reaction in the synthesis of a biologically active carbacepham [9]. The photolysis of acyclic 5-phenyl-1-pentanol nitrite gives, preferentially, a nitroso dimer arising as a result of the abstraction of a hydrogen attached to the d-carbon, rather than the e-carbon from which the better stabilized benzyl radical can be generated (Scheme 10) [10].

The use of tin hydrides has increased the power of radical reaction in organic synthesis tremendously, and all of the steps in these radical chain processes have been studied in great detail because of the importance of the reactions. We won t dwell excessively on these details, but we need to go back and re-examine some points about this reaction because there are some further subtleties that you need to understand. 

The past 5 years study of the radical-polar crossover reaction has led to a rich vein of new chemistry and intriguing reactions. This type of reaction is still in its infancy, and many facets remain to be explored. However, the use of radical-polar crossover chemistry as the key reaction in the synthesis of aspidospermidine demonstrates the utility of the process in a challenging molecular setting. 

The use of Lewis acids to impart chemoselectivity and stereoselectivity to free-radical polymerization and copolymerization is well documented [670]. Recent progress in radical reactions in organic synthesis has revealed the importance of Lewis acids in selective transformations [671,672]. Lewis acids have also been found to enhance the reactivity both of radical acceptors [673-675] and of radicals themselves [676], thus increasing the efficiency of radical reactions. 

Both intermolecular and intramolecular additions of carbon radicals to alkenes and alkynes continue to be a widely investigated method for carbon-carbon bond formation and has been the subject of a number of review articles. In particular, the inter- and intra-molecular additions of vinyl, heteroatomic and metal-centred radicals to alkynes have been reported and also the factors which influence the addition reactions of carbon radicals to unsaturated carbon-carbon bonds. The stereochemical outcome of such additions continues to attract interest. The generation and use of alkoxy radicals in both asymmetric cyclizations and skeletal rearrangements has been reviewed and the use of fi ee radical reactions in the stereoselective synthesis of a-amino acid derivatives has appeared in two reports." The stereochemical features and synthetic potential of the [1,2]-Wittig rearrangement has also been reviewed. In addition, a review of some recent applications of free radical chain reactions in organic and polymer synthesis has appeared. The effect of solvent upon the reactions of neutral fi ee radicals has also recently been reviewed. ... 

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