Barton method radical addition reactions

Thioethers have also been prepared on cross-linked polystyrene by radical addition of thiols to support-bound alkenes and by reaction of support-bound carbon radicals (generated by addition of carbon radicals to resin-bound acrylates) with esters of l-hydroxy-l,2-dihydro-2-pyridinethione ( Barton esters Entry 6, Table 8.5). Additional methods include the reaction of metallated supports with symmetric disulfides (Entries 7-9, Table 8.5) and the alkylation of polystyrene-bound, a-lithiated thioani-sole [65],... 

The basic transformation that underlies the Barton method is outlined in Scheme 45, steps 1 and 2.152 Thermolysis in refluxing toluene or photolysis with a sunlamp rapidly converts a thiohydroxamate ester (32) to the decarboxylated pyridyl sulfide (33). This pyridyl sulfide is formed by addition of an alkyl radical R to the thiohydroxamate (32) followed by fragmentation of (34) as indicated. In the planning of addition reactions by the Barton method, it is usually assumed that the addition step 1 is rate limiting. However, there is now evidence that step 1 may sometimes be reversible and step 2 may be rate limiting.153... 

Alkoxyl radicals can be generated by a variety of methods including peroxide reduction, nitrite ester photolysis, hypohalite thermolysis, and fragmentation of epoxyalkyl radicals (for additional examples of alkoxyl radical generation, see Section 4.2.S.2). Hypohalites are excellent halogen atom donors to carbon-centered radicals, and a recent example of this type of cyclization from the work of Kraus is illustrated in Scheme 43.182 Oxidation of the hemiketal (57) presumably forms an intermediate hypoiodite, which spontaneously cyclizes to (58) by an atom transfer mechanism. Unfortunately, the direct application of the Barton method for the generation of alkoxyl radicals fails because the intermediate pyridine-thione carbonates are sensitive to hydrolytic reactions. However, in a very important recent development, Beckwith and Hay have shown that alkoxyl radicals are formed from N-alkoxypyridinethiones.183 Al-... 

Sequences in which addition precedes cyclization are not as straightforward to conduct as the reverse however, they are very important because a net annulation results (that is, a new ring is formed by the union of two acyclic precursors in one experimental step). The intermediate radical is differentiated from the other radicals provided that the cyclization reaction is rapid, but it can be difficult to differentiate the initial radical from the final radical. As illustrated in Scheme 57, this is particularly true in the tin hydride method because many different types of radicals react with tin hydride at similar rates. Reaction of (69) under standard radical addition conditions produces (70), which results from a sequence of addition/cy-clization/addition.233 That the last C—C bond is formed actually results from a lack of selectivity the initial and final radicals are not differentiated and they must undergo the same reaction. Of course, this lack of selectivity is of no consequence if the product contains the desired skeleton and the needed functionality for subsequent transformations. Such sequences are very useful for forming three carbon-carbon bonds, and they can also be conducted by Barton s thiohydroxamate method.234 Structural modifications are required to differentiate the initial and final radicals, and, as illustrated by the conversion of (71) to (72), phenyl groups can provide the needed differentiation (probably by retarding the rate of addition more than they retard the rate of hydrogen abstraction). Clive has demonstrated that phenyl-substituted vinyl radicals also provide the needed selectivity, as illustrated by the second example in Scheme 57.233... 

Stereoselective C—C bond formation also occurs in the addition of chiral dimethylpyrrolidine amide substituted radicals to ethyl acrylate2, The radicals are generated via irradiation of alkyl thiohydroxamates ( Barton method )3. Reactions at different temperatures yield isomeric mixtures of monoadducts (35-50%) and diadducts (15-25%). High levels of asymmetric induction are observed in the production of the monoadduct. The diadduct is a 1 1 mixture of C-4 diastereomers, presumably possessing the S configuration at C-2. 

Boron trifluoride catalyses the 1,3-phosphotropic rearrangement of the a-phosphorylated imine (65) to give (66).35 This reaction takes place at room temperature, whereas the uncatalysed reaction requires heating to 150-2000C. High yields of the addition products (67) have been obtained from the reaction of carbon-centred radicals with diphenylvinylphosphine oxide.36 Radical addition to the chiral phosphine oxides (68) using Barton s method provides diastereomeric ratios of up to 9 1 in the case of (69). 

As exemplified in the following cases, this addition reaction has often been used as the first step in the preparation of vinyl sulfones. The adduct must therefore undergo a subsequent elimination reaction. A base is needed to perform dehydrohalogenation. The selenides resulting from the addition of selenosul-fonates can be eliminated very smoothly through oxidation. Thus, Yus and co-workers [104] have based a very simple method for the preparation of j9-sulfonyl-a,j9-unsaturated compounds on the addition of tosyl iodide to Michael acceptors (equation (50)) whereas Barton et al. [105] have shown that the addition of phenylseienotosylate to electron-rich olefins, catalyzed by Ru(II) complexes, is efficient (equation (51)). An alternative approach is the Ce(IV)-mediated addition of arylsulfinates to electron-rich olefins which proceeded directly to the olefinic product resulting from oxidative elimination of the intermediate alkyl radical (equation (52)) [106]. 

Although Barton reactions occur more easily with rigid structures flexible molecules can also be functionalized by this method. The reaction of the acyclic system 46 shown below must involve a rapid hydrogen atom abstraction from C-5, since cyclic products derived from the addition of the oxygen radical to the double bond are not observed. ... 

The difficulties inherent in the original Hunsdiecker reaction and its modifications stimulated the development of an additional halo-decarboxylation method that involves treatment of thiohydroxamic esters of carboxylic acids with BrCCls, ICH3 or CH2I2 in the presence of a radical initiator (Route 3, Barton reaction, Figure 10.23). 

The Hunsdiecker Reaction. The classical Hunsdiecker reaction is somewhat restricted due to the relatively harsh conditions required. In the Barton version, alkyl radicals generated from O-acyl thiohydroxamates, under either thermal or photolytic conditions, are efficiently trapped either by CI3C-X (X=C1 or Br CbC is the chain carrier) or by IodoformThe method is applicable to sensitive substrates for which the classical methods are unsuitable. thus allowing the preparation of a wide range of alkyl chlorides, bromides, and iodides by the one-carbon degradation of a carboxylic acid. Similar reactions of aromatic acid derivatives tend to require an additional radical initiator (e.g. Azo-bisisobutyronitrile), if high yields (55-85%) are to be obtained. ... 

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