Addition of nucleophilic radicals

The regioselectivity in radical addition reactions to alkenes in general has successfully been interpreted by a combination of steric and electronic effects1815,47. In the absence of steric effects, regiochemical preferences can readily be explained with FMO theory. The most relevant polyene orbital for the addition of nucleophilic radicals to polyenes will be the LUMO for the addition of electrophilic orbitals it will be the HOMO. Table 10 lists the HOMO and LUMO coefficients (without the phase sign) for the first three members of the polyene family together with those for ethylene as calculated from Hiickel theory and with the AMI semiempirical method48. 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

Substitution at the terminal position of the allylstannane, as in crotonyltributyl stannane, however, is not tolerated, because hydrogen abstraction from the allylic position is a competing reaction [21], An extension of the method involves the coupling of the anomeric radical precursors 28 with the allyltributyltin reagent 29 [14], In the reagent 29 the double bond is activated toward addition of nucleophilic radicals by the electron-withdrawing t-butoxy carbonyl group. The obtained product 30 has been useful en route to 3-deoxy-D-marmo-2-octulosonic acid (KDO). 

Addition of nucleophilic radicals to protonated heteroaromatics (the Minisci reaction) 768... 

A large number of accurate rate constants are known for addition of simple alkyl radicals to alkenes.33-33 Table 2 summarizes some substituent effects in the addition of the cyclohexyl radical to a series of monosubstituted alkenes.36 The resonance stabilization of the adduct radical is relatively unimportant (because of the early transition state) and the rate constants for additions roughly parallel the LUMO energy of the alkene. Styrene is selected as a convenient reference because it is experimentally difficult to conduct additions of nucleophilic radicals to alkenes that are much poorer acceptors than styrene. Thus, high yield additions of alkyl radicals to acceptors, such as vinyl chloride and vinyl acetate, are difficult to accomplish and it is not possible to add alkyl radicals to simple alkyl-substituted alkenes. Alkynes are slightly poorer acceptors than similarly activated alkenes but are still useful.37... 

Additions to aromatic rings can become useful when radicals and acceptors are electronically paired. The additions of electrophilic radicals to electron rich aromatic rings are growing in importance and the additions of nucleophilic radicals to electron poor alkenes have long been of preparative value. This chapter can provide only a few representative examples of each class. Giese s book is recommended as a more thorough overview of additions to aromatic rings.232... 

More recently, Porta and co-workers [6] applied similar considerations of the polar effects to a new one-pot multicomponent process for the addition of nucleophilic radicals to aldimines, generated in situ in the presence of Ti(IV). In analogy with the Minisci reaction, Ti(IV), which acts as a Lewis acid, coordinates the nitrogen of the imine, strongly increasing the electron-deficient character of the carbon in the a-posilion and thus the reactivity of the imine toward nucleophilic radicals. This reaction, as well as the Minisci one, represents a useful route for the synthesis of a variety of poly-functionalized derivatives of chemical and biochemical relevance. 

The general reaction mechanism is shown in Scheme 2. The high rate constants (from 10s to 108 m 1 s 1) for addition of nucleophilic radicals to protonated heterocycles [3] reduce other possible competitive side reactions of the radicals involved, strongly contributing to the synthetic interest. 

For addition of nucleophilic radicals to an alkene, the dominant interaction is between the SOMO of the radical and the LUMO of the olefin. Complexation of a Lewis acid to the alkene lowers its LUMO and magnifies the SOMO-LUMO interaction [3a]. Thus, one expects that the rate of addition of carbon radicals to alkenes should be dependent on the presence of Lewis acid if that alkene is capable of complexation to Lewis acid. The important processes for such a reaction are shown in Eqs. (7)-(9). 

This began to happen in the early to mid 1980s. And, thanks to the solid foundation, synthetic radical chemistry blossomed with amazing speed. Giese s reductive additions of nucleophilic radicals to alkenes convincingly showed the synthetic community that radical additions to alkenes do not have to result in polymerization... 

Several groups have employed 1,4-additions of nucleophiles, radicals or silanes to allyl acrylates. The intermediate sUyl ketene acetals then underwent Ireland-Claisen rearrangement (Scheme 4.55). 

Aluminum Lewis acid was also used in asymmetric radical addition of nucleophilic radical including alkyl radical to a,p-unsaturated carbonyls. Yonemitsu and CO workers reported diastereoselective radical cyclizationof alkynylacrylate equipped with 8-phenylmenthyl chiral auxiliary (Scheme 6.171) [201]. 

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