Retrosynthetic analysis radical reactions

Rather recently, Curran has published an important account of radical reactions and retrosynthetic planning [29], in which he introduces a convenient symbolism in order to incorporate radical reactions into standard retrosynthetic analysis. 

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. 

As radical reactions are increasingly applied in synthesis, a convenient and informative method to notate these reactions in retrosynthetic analysis becomes desirable. Currently, two fragments united by a radical reaction are sometimes represented simply by dots Seebach has introduced the radical syn-thon, notated as r (Scheme 18).74 Both of these notations have two related limitations first, they imply that C—C bonds are formed by radical-radical coupling, and second, they do not indicate which site provided the radical and which site accepted it. I introduce here a notation for radicals in retrosynthetic analysis that strives to be in harmony with current ionic notations without artificially imposing75 on radical reactions the features needed for the planning of ionic reactions. 

Retrosynthetic analysis of nitrile 164 disconnects the C-CN bond because it is clear that the six carbons of the methylcyclopentene starting material are more or less intact in the remainder of the molecule. This disconnection requires a C-C bond-forming reaction involving cyanide. Because cyanide is associated with a carbon nucleophile, assign Cj to the cyanide and to the cyclopentene carbon. The synthetic equivalent for Cg is an alkyl halide, and 2-bromo-l-methylcyclopentane (168) is the disconnect product. Bromide 168 is obtained directly from the alkene starting material, but it requires the use of a radical process to generate the anti-Markovnikov product (see Chapter 10, Section 10.8.2). 

The serious limitations in e syn esis of the aryl acetic acid 7, required the development of a better alternative. Retrosynthetic analysis of the aryl acetic acid led us to conqwund 21 as a possible starting material. Coinpound 21 is prepared from the commercially available and inexpensive 2,5-dimethoxy dibydrofivan 20 by free radical addition of malonic ester. Conqiound 21 was obtained in commercial quantities from a vendor but the purity was <40%. Reaction of crude 21 with p-(p-cyanophenyl)aniline (5) afforded the aryl malonic ester 22. This was hydrolyzed to the diacid, following a solvent exchange with dioxane to remove the methanol, and decarboxylated with hydrochloric acid at 90 C to give the aryl acetic acid in a one-pot operation (Scheme 4). The aryl acetic acid obtained in tiiis process was >98% pure. 

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