Barton esters addition reactions

Note 2), and 40 mL of methylene chloride (Note 3). The resulting homogeneous solution is cooled to 0°C and 4.99 g (27.1 mmol) of 10-undecenoic acid (1) is added dropwise (Note 4). Following the addition of the undecenoic acid, the ice bath is removed and the reaction mixture is allowed to warm to room temperature and stirred for a further 8 hr. The bright yellow suspension that results is filtered through a bed of silica gel (Note 5). The solvent is removed under reduced pressure to give 8.06 g of the crude Barton ester (3) (Notes 6 and 7). 

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],... 

Scheme 44 summarizes an addition reaction by the Barton method. Thiohydroxamate esters (32) are readily prepared and isolated, but, more typically, they are generated in situ. Experimental procedures have been described in detail148151 and often entail the slow addition of an acid chloride to a refluxing chlorobenzene solution of the readily available sodium salt (31), dimethylaminopyridine (DMAP, to catalyze the esterification), and excess alkene. The products are usually isolated by standard aqueous work-up and chromatographic purification. 

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... 

Since Barton decarboxylation can be performed under mild conditions, thermal or photolytic treatment of the Barton ester (13) of propionic acid with TV-hydroxy-2-thiopyridone in the presence of chiral menthyl acrylates generates addition products (14). However, diastereoselectivity is rather poor, since the chiral menthyl center is too far away from the C-C bond-forming position, as shown in eq. 10.7. When the chiral center is adjacent to the reaction position, stereocontrol is significantly affected, as shown in eq. 10.8 [9-12]. 

Barton and Crich reported the first examples of the uses of 2-substituted allylic sulfur compounds [53]. Their initial experiments with additions of simple alkyl radicals to allyl sulfides, sulfoxides and sulfones were relatively unsuccessful. This failure was largely due to the fact that the nucleophilic alkyl radicals, which were generated by photolysis of the corresponding Barton ester, underwent addition to a second equivalent of Barton ester faster than they added to the allyl transfer agent. Reactions were much more successful with the electron-deficient acrylate reagent 93 (Fig. 4). Crich was later able to show that this same reagent underwent addition reactions with an acyl radical derived from an acyl phenyl telluride [54]. 

An excellent alternative to the classical Hunsdiecker reaction and its variants, which totally avoids the use of heavy metal salts and potent electrophilic reagents, consists of the simple photolysis or thermolysis of Barton esters in refluxing bromotri-chloromethane for the bromides or tetrachloromethane for the chlorides [4], The analogous decarboxylative iodination can also be achieved using iodoform as the reagent in a benzene/cyclohexene solvent system (Scheme 5). For the cases of vinylic and aromatic acids, where the usual problems of chain efficiency are encountered, the addition of azobisisobutyronitrile (AIBN) is also required [10]. Nevertheless, since this method can operate on both electron-rich and electron-poor aromatic systems, and moreover does not suffer from the competitive electrophilic aromatic bromination found with electron rich aromatics under normal Hunsdiecker conditions, this route to synthetically useful aryl iodides and bromides should find widespread application. 

The carbohydrate-based ether auxiliaries have been used to develop a radical-based asymmetric aldol reaction. Glycoside radicals such as 37 are generated from Barton ester precursors 39 [40], and the addition of these radicals to 2-nitropropene gives a thiopyridyl adduct 40 that can be converted to an aldol product [41]. The yield for the conversion is moderate to good and the diastereoselectivity ranges from 5 1 to 8 1, depending on R and temperature. 

Biehl s group [97] has developed an efficient syntesis of benzo[4,5]thieno [2,3- ]pyridines and appropriate naphthyl-analogues by reaction of in situ generated benzyne with Barton esters. For example, when the acetone solution of anthranilic acid (58) was added dropwise to the refluxing mixture of the Barton ester 527 and isopentyl nitrite in dichloromethane, after an additional 3-h refluxing period, the respective benzo[4,5]thieno[2,3-A]pyridine (528) was obtained in 52% yield. Scheme 52. 

Section 12.5 in Part A describes some additional reactions that are of synthetic value and involve intramolecular hydrogen abstraction at unactivated groups. Of particular note is a method, known as the Barton reaction, in which nitrite esters of alcohols are photolyzed. Nearby hydrocarbon groups, including methyl groups, can be functionalized by this method, and the reaction has been applied to remote functionalization in steroids. 

Barton esters were used in a number of standard and also in more complex free-radical transformations including substitution, fragmentation/elimination, and addition reactions. Some representative examples are collected in the following sections. 

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-... 

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