Free radicals, Barton esters

Pyridine-2-thione-A-oxycarbonyl (PTOC) derivatives of carboxylic esters 53 were developed by Barton et al. and serve as a convenient source of acyloxyl radicals, which upon decarboxylation provide specific routes to free radicals (equation 82). This process can also proceed by a radical addition (equation 83). Acyl selenides (54) are a convenient source of acyl radicals, which can undergo decarbonylation also giving specific free radicals (equation 84). ° ... 

When a free radical is formed and held tightly within a molecule, reactions of quite high site specificity (regioselectivity) may be observed. The free radical may be generated from another functional group in the molecule, but the result is the substitution at a centre that in a formal sense has the characteristics of a hydrocarbon. Such reactions are observed in the photolysis of nitrite esters (RONO) (the Barton reaction), the... 

Ammonium formate hydrogenolysis of 7t-allyl-palladium(II) complexes formed via oxidative addition of Pd(0) to propargylic carbonate esters is a useful method for preparing disubstituted alkynes, as depicted below. This method of deoxygenation avoids the use of expensive and toxic reagents often associated with the free-radical Barton-McCombie deoxygenation. °... 

Girard, P., Guillot, N., Motherwell, W. B., Hay-Motherwell, R. S., Potier, P. The reaction of thionitrites with Barton esters a convenient free radical chain reaction for decarboxylative nitrosation. Tetrahedron 1999, 55, 3573-3584. 

The pyridinethiones (197) are a useful source of alkoxy radicals upon irradiation. The bond fission processes are brought about by irradiation at 350 nm and the resultant radicals have been demonstrated to react effectively with guanine. A study of the isomeric iV-hydroxypyridine-4-thione has also been reported. N-O bond fission has been studied in iV-phenylhydroxy-lamine. Derivatives of this type have been used frequently as sources of free radicals. For example, the Barton esters (198) have been used to form a-amido radicals. The kinetics of rotation around the C-N bond within these have been measured. Other studies have examined cyclisations within radicals produced from Barton esters. ... 

In terms of generation and manipulation of O-acyl thiohydroxamates it is important to recognize that, in the absence of any other reagents, decarboxylative rearrangement to alkyl-2-pyridyl sulfides can occur (Scheme 7). This is the simplest free-radical reaction of Barton esters and is of preparative utility in its own right. A series of crossover experiments demonstrated that the only mechanism which oper-... 

The above transformation is a particularly useful one which would require several steps by conventional methodology. Two distinctly different methods, both of which depend on the free-radical chain reactions of Barton esters, have however been developed. 

A second, closely related experiment was conducted with the Barton ester 6 [4]. Here, the results were cleaner owing to the stronger C-H bonds, which effectively eliminated the deprotonation pathway and the formation of any allyl radicals. Moreover, as expected, because of the electron-donating effect of the para-methoxy group the diffusively free radical cation 8 could now be observed even in pure acetonitrile (Scheme 2). However, the telling feature of this series of experiments was... 

Side-chain halogenated amino acid derivatives are reduced, deuterated, allylated and alkylated with stannanes and related reagents in free-radical processes [53]. Other side-chain functional groups may also be manipulated to produce amino acid radicals [8, 54-58], and, in particular. Barton decarboxylation of aspartate and glutamate derivatives has been applied in this manner (Scheme 8) [55]. Related procedures have been developed to generate amino acid radicals by dehydrox-ylation of hydroxy amino acid derivatives [56]. Hydroxy amino acid derivatives may also be converted to nitrate esters, from which the corresponding alkoxy radi-... 

Selenopenams have been synthesized via free radical homolytic substitution of aryl or alkyl radicals at the selenium atom. Refluxing the Barton ester 119 R = Me in benzene gave the selenocycle 120 R = Me in low yield. Alternatively, if 119, R = H, is irradiated (250W, tungsten lamp) the selenopenam 120 R = H is produced in moderate yield. 

Thiohydroxamic esters, such as V-hydrox5q)5nidine-2-thione, were first used as free radical precursors by Barton. " The decomposition of such esters by heat or visible light yields acyloxy radicals and pyridine thiol radicals. However, on irradiation at low-temperature, the chain reaction is essentially suppressed. 

Masterson DS, Porter NA (2002) Diastereoselective free radical halogenation, azidation, and rearrangement of P-silyl barton esters. Org Lett 4(24) 4253-4256... 

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. 

Remarkably, only a small number of intramolecular reactions utilize Barton esters " - likewise, the use of the Barton chemistry in making CC bonds in tandem or domino reactions is far less exploited compared to the tin-hydride-mediated free-radical sequences. The following example is taken from the biomimetic conversion of isoflavone to the rotenoid, where the reaction affords the 6-endo product (Scheme 24). ... 

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 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... 

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