Substitution reactions, radical-mediated

As indicated in Chapter 8, the production of alkanes, as by-products, frequently accompanies the two-phase metal carbonyl promoted carbonylation of haloalkanes. In the case of the cobalt carbonyl mediated reactions, it has been assumed that both the reductive dehalogenation reactions and the carbonylation reactions proceed via a common initial nucleophilic substitution reaction and that a base-catalysed anionic (or radical) cleavage of the metal-alkyl bond is in competition with the carbonylation step [l]. Although such a mechanism is not entirely satisfactory, there is no evidence for any other intermediate metal carbonyl species. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

By far the most generally useful synthetic application of allyltributyltin is in the complementary set of transition metal- and radical-mediated substitution reactions. When the halide substrates are benzylic, allylic, aromatic or acyl, transition metal catalysis is usually the method of choice for allyl transfer from tin to carbon. When the halide (or halide equivalent) substrate is aliphatic or alicyclic, radical chain conditions are appropriate, as g-hydrogen elimination is generally not a problem in these cases. 

Alkanes can be prepared by the addition of carbon radicals to C=C double bonds (Figure 5.4). The highest yields are usually obtained when electron-rich radicals (e.g. alkyl radicals or heteroatom-substituted radicals) add to acceptor-substituted alkenes, or when electron-poor radicals add to electron-rich double bonds. These reactions have also been performed on solid phase, and polystyrene-based supports seem to be particularly well suited for radical-mediated processes [39,40]. 

The aim of the present article is to survey a radical-mediated reaction by which bromine atoms may be substituted directly into some carbohydrate derivatives at ring positions by the following general mechanism. 

In this case, the intermediate vinyl radical (cf Scheme 9) underwent a remarkable [1,51-hydrogen abstraction from the non-activated C—H bond of the proximal isopropyl group. Furthermore, the resulting primary alkyl radical underwent a unique, stereoselective 5-endo-trig cyclization onto the adjacent double bond to generate a tertiary radical, which is a precursor of the highly substituted cyclopentanols 22 and 23. The reaction with Bu3SnH as radical mediator totally reversed the products ratio obtained in 88% yield, i.e. 22 23 = 19 81. 

To be effective as autoxidation inhibitors radical scavengers must react quickly with peroxyl or alkyl radicals and lead thereby to the formation of unreactive products. Phenols substituted with electron-donating substituents have relatively low O-H bond dissociation enthalpies (Table 3.1 even lower than arene-bound isopropyl groups [68]), and yield, on hydrogen abstraction, stable phenoxyl radicals which no longer sustain the radical chain reaction. The phenols should not be too electron-rich, however, because this could lead to excessive air-sensitivity of the phenol, i.e. to rapid oxidation of the phenol via SET to oxygen (see next section). Scheme 3.17 shows a selection of radical scavengers which have proved suitable for inhibition of autoxidation processes (and radical-mediated polymerization). 

A cycloaddition methodology has been exploited in the cation radical-mediated reactions between electron-rich chalcone epoxides 287 and A -aryl imines 286 using tris(4-bromophenyl)aminium hexachloroantimonate (TBPA -SbCle ) as the radical initiator to generate substituted 1,3-oxazolidines 288a and 288b in good yields (Equation 21) <2005SL161>. 

An interesting result of control of acyclic stereochemistry is reported by Nagano et al. [57], who showed that efficient 1,2-asymmetric induction can be achieved in radical-mediated allylation of diethyl (25,35)-3-bromo-2-oxo-succinates stereoselectively. In the Eu(fod)3 (1.1 equivalent) photocatalyzed reaction of bromohydroxy compound (4) diastereoselectivity is reversed with respect to the simple photoreaction. On the other hand, substitution with silyl groups tends to enhance diastereoselectivity up to 8.6 1. The effect is still operative to a lesser extent with catalytic amounts of the lanthanide reagent (0.1 equivalents, threo/erythro [5/6] = 3 1) (eq. (2)) [57]. 

The mechanism of photoinduced oxidation of aromatic compounds mediated by Ti02 in aqueous media is demonstrated by the reaction of 4-chlorophenol (601). Its degradation is principally based on oxidation by photocatalytically produced hydroxyl radicals, most likely adsorbed on the surface of a semiconductor catalyst.1554,1555 The initial reaction affords a 4-chlorodihydroxycyclodienyl radical 602, which releases the chlorine atom to form hydroquinone in a radical substitution reaction or loses the hydrogen atom via... 

It is worth noting that the same kind of reactions can be carried out by tin-radical-mediated ring closure of analogous isothiocyanates e.g., 33, 37, 39, NC = NCS) [22b,c], In this case, the intermediate a-thio-substituted imidoyl radical is generated by addition of a stannyl radical to the sulfur atom of the isothiocyanate. Although it had been known for a few decades, this way to imidoyl radicals had found very little application in organic synthesis. Bachi s work was the first example of synthesis of heterocyclic compounds by radical addition to isothiocyanates, showing the way to further possible applications [9]. 

BusSnH-mediated intramolecular arylations of various heteroarenes such as substituted pyrroles, indoles, pyridones and imidazoles have also been reported [51]. In addition, aryl bromides, chlorides and iodides have been used as substrates in electrochemically induced radical biaryl synthesis [52]. Curran introduced [4-1-1] annulations incorporating aromatic substitution reactions with vinyl radicals for the synthesis of the core structure of various camptothecin derivatives [53]. The vinyl radicals have been generated from alkynes by radical addition reactions [53, 54]. For example, aryl radical 27, generated from the corresponding iodide or bromide, was allowed to react with phenyl isonitrile to afford imidoyl radical 28, which further reacts in a 5-exo-dig process to vinyl radical 29 (Scheme 8) [53a,b]. The vinyl radical 29 then reacts in a 1,6-cyclization followed by oxidation to the tetracycle 30. There is some evidence [55] that the homolytic aromatic substitution can also occur via initial ipso attack to afford spiro radical 31, followed by opening of this cyclo-... 

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