Barton esters fragmentation

Other pathways of radical generation involve thermal or photochemical fragmentation of perfluoroacyl peroxides [14] or photochemical fragmentation of perfluoro-alkylsulfonyl bromides [15]. The in situ formation of Barton esters from perfluoroacyl chlorides and thiopyridone-N-oxide has also been used as a convenient source of radicals [16] (Scheme 2.99). 

Scheme 15 Mechanism of addition-fragmentation chain transfer with Barton ester (58). Reproduced from Moad, G. Rizzardo, E. Thang, S. H., Radical addition-fragmentation chemistry in polymer synthesis. Polymer 2008,49,1079-1131. ...

Tin Hydride-Mediated Reaction Allyltin Method Photochemical Fragmentation of Barton Esters Direct Photolysis of Cobaloximes Direct Photolysis of Organotellurium Compounds Miscellaneous... 

According to the classical definition. Barton esters are mixed anhydrides of carboxylic acids with thio-hydroxamic acid such as I (Scheme Ij. This class of compound was originally developed to allow the transformation of carboxylic acids to a convenient source of radicals for synthetic application. Even now, they are one of the most important entries to C-radicals. Over time, the scope of the reaction was broadened, allowing the generation of heteroatom-centered radicals, particularly oxyl-, aminyl-, and iminyl radicals of synthetic interest. For these transformations, carbonates and carbamates (II), acetates (IV), and ethers (V) were developed (Scheme 1). Finally, oxalates (III) were used for deoxygenation of secondary and tertiary alcohols. The radical fragmentation reaction of these compounds can be carried out either by irradiation or by thermal activation. Both methods are discussed here briefly. 

The thione function of the Barton ester 1 can be replaced by other elements such as Se (13) without significant alteration of the reactivity (Scheme 6). Although the starting esters are more air sensitive than the analogous N-hydroxypyridine 2-thione derivatives (1), the method has some advantages for example, the adducts of the free-radical fragmentation reactions of N-hydroxypyridine-2-selenone derivatives 13 (i.e., alkylpyridylselenides) can usually be more easily modeled and transformed to other chemical functions than thioethers. 

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. 

Free radicals generated under photochemical conditions from thiohydroxamates add readily to the NN double bond of diaziridines and in particular to the 3-bromo or 3-trifluoromethyl-3-phenyldiazirine to produce diaziridinyl radicals (Scheme 25) these intermediates undergo dimerization and fragmentation to yield the corresponding imines, which can be hydrolyzed to the corresponding amines. Barton esters can also be used for the direct preparation of nitroso compounds. From a synthetic standpoint, the yields are moderate and the method is limited to primary and secondary carboxylic acids, which form dimers as an end product. Tertiary nitroso compounds do not dimerize and further react with the radical present under the reaction conditions. 

There is quite some evidence for a mechanism as formulated above,especially for the six-membered transition state—the Barton reaction is observed only with starting materials of appropriate structure and geometry, while the photolysis of nitrite esters in general seldom leads to useful products formed by fragmentation, disproportionation or unselective intermolecular hydrogen abstraction. 

Organic chemists have been aware of reversible addition-fragmentation involving xanthate esters in organic chemistry for some time. It is the basis of the Barton-McCombie process for deoxygenation of alcohols (Scheme 9.37).402 404... 

Radicals formed by fragmentation of xanthate and related thiono esters can also be trapped by reactive alkenes.217 The mechanism of radical generation from thiono esters was discussed in connection with the Barton deoxygenation method in Section 5.4. 

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-... 

The driving force for the fragmentation is formation of the C=0 double bond. If R reacts with Bu3SnH, a tributyltin radical is produced which continues the chain. Carried out in this manner this reaction is called the Barton deoxygenation of alcohols, since alcohols are precursors for the thiono esters. 

There are a variety of photochemical reactions involving free nitrous oxide (NO) as persistent radical. Often there is an initial fragmentation, as presented in Scheme 6 for TV, 7V-dimethyl-/V-nitro-samine. One example is the Barton reaction of nitrite esters (Scheme 15). It allows the functionalization of methyl groups in steroids and utilizes an intermediate 1,5-hydrogen atom migration, which converts the initially formed oxygen-centered radical to a carbon-centered species.69... 

Barton has devised such a pathway for converting carboxylic acids to hydroperoxides via A -hydroxypyridine-2-thione esters [16a,b] (Scheme 5). The yields of hydroperoxides are 45-89% [16]. Reduction of the crude products with trimethyl phosphite (rt) or dimethyl sulfide (80 °C) readily provides the corresponding alcohols. On the other hand, tosylation and ensuing Kornblum-De La Mare type fragmentation [17] leads to carbonyl compounds [16b] (Scheme 5). 

In addition to dehydroxylation, a useful protocol for decarboxylation has been developed. The procedure was introduced by Barton, using thiohydroxamic esters 9, prepared from activated carboxylic acids (RCOX) and the sodium salt of N-hydroxypyridine-2-thione. Simple thermolysis or photolysis of the esters (homolysis of the N—O bond) results in the production of alkyl radicals R, which can attack the sulfur atom of the thiocarbonyl group to propagate the fragmentation (4.9). 

Oxidation Reactions. Hypoiodite intermediates may be generated from the reaction of simple alcohols with NIS. When conducted under photochemical irradiation, the products of Barton-type or fragmentation reactions of alkoxyl radical intermediates may be obtained. Aldehydes are oxidized to methyl esters via hemiacetal intermediates by reaction with NIS in methanol at rt. However, such conditions are not effective for the oxidation of simple alcohols. The combination of NIS and Tetrabutylammonium Iodide in dichloromethane has been developed for the oxidation of a variety of alcohols to the corresponding carbonyl corrpounds (eq 8). This reagent system is most widely used for the oxidation of lactols to lactones, in which near-quantitative yields are generally obtained under mild conditions (eq 9). ... 

Self-catalyzed transesterification with 2-dimethylaminoethanol in DMF has been found effective in cleaving protected peptides from the Mer-rifield resin, in the absence of side-chain benzyl ester protecting groups (Barton et al., 1973). This mild, virtually racemization-free procedure may prove extremely useful for fragment condensation because it yields N-Z-and iV-Boc-protected peptides. Since the reagent, 2-dimethyl-amino-ethanol, specifically cleaves of the benzylic ester group, the benzyl esters of glutamic acid and aspartic acid, if present, will also be hydrolyzed (Barton et al., 1973 Savoie and Barton, 1974). 

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