Radical deoxygenation of alcohols the Barton reaction

The radical deoxygenation of secondary alcohols through tri-n-butyltin hydride reduction of their xanthate derivatives was introduced in 1975 [227], The reaction proceeds by thiophilic radical addition to the thiocarbonyl group of a tin radical followed by collapse of the carbon intermediate, as shown in the accompanying scheme. Hydrogen transfer completes the process. 

After some controversy [228], the mechanism was confirmed by a 119Sn NMR study. 

A number of other thiocarbonyl derivatives have been used [222] (sec below), as well as various hydrogen atom sources (tin and silicon hydrides, 

The starting material was easily prepared from cholestanol and the commercially available 4-fluorophenyl chlorothionoformate. 

To the solution of the thionocarbonate (217 mg, 0.4 mmol) in dry dioxane (3 ml), dimethyl phosphite (180 ml, 2.0mmol) was added under argon. Then the solution was brought to the boil and treated with portions (150 ml) of a solution of benzoyl peroxide (387 mg dissolved in 3.0 ml of dry dioxane) at 30 min intervals. The reaction was monitored by TLC. When the reaction was complete (2 h) the solvent was removed under vacuum and the product isolated by column chromatography on silica gel (eluent hexanes), giving cholestane (135 mg, 91%). 

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The addition of silyl radicals to thiocarbonyl derivatives is a facile process leading to a-silylthio adducts (Reaction 5.37). This elementary reaction is the initial step of the radical chain deoxygenation of alcohols or Barton McCombie reaction (see Section 4.3.3 for more details). However, rate constants for the formation of these adducts are limited to the value for the reaction of (TMS)3Si radical with the xanthate c-C6HuOC(S)SMe (Table 5.3), a reaction that is also found to be reversible [15]. Structural information on the a-silylthio adducts as well as some kinetic data for the decay reactions of these species have been obtained by EPR spectroscopy [9,72]. 

Radical deoxygenation of alcohols is important, and the reduction of xanthates prepared from alcohols, with Bu3SnH in the presence of AIBN is called the Barton-McCombie reaction (eq. 2.13) [37-51]. The driving force for the reaction is the formation of a strong C=0 bond from the C=S bond, approximately 10 kcal/mol stronger. This reaction can be used for various types of substrates such as nucleosides and sugars. Though methyl xanthates, prepared from alcohols with carbon disulfide and methyl iodide under basic conditions are very frequently used, other thiocarbonates, as shown in eq. 2.14, can also be employed. 

Deoxygenation of alcohols.1 This reaction can be effected by conversion of an alcohol to a derivative that undergoes radical reduction by a hydrogen atom donor (Barton-McCombic reaction). Xanthates are usually employed as the intermediate but... 

A relevant reductive process, which has found wide application in organic synthesis, is the deoxygenation of alcohols introduced in 1975 by Barton and McCombie [58]. Reaction (4.28) shows that the thiocarbonyl derivatives, easily obtained from the corresponding alcohol, can be reduced in the presence of BusSnH under free radical conditions. The reactivity of xanthates and thiocarbonyl imidazolides [58] was successfully extended to 0-arylthiocarbonates [59] and (9-thioxocarbamates [60]. Several reviews have appeared on this subject, thus providing an exhaustive view of this methodology and its application in natural product synthesis [61-64]. 

Primary alcohols (a) D. H. R. Barton, W. B. Motherwell, and A. Stange, Radical-induced deoxygenation of primary alcohols, Synthesis, p. 743 (1981) (b) D. H. R. Barton, P. Blundell, J. Dorchak, D. O. Jang, and J. C. Jaszberenyi, The invention of radical reactions. Part XXI. Simple methods for the radical deoxygenation of primary alcohols, Tetrahedron 47 8969 (1991). 

D. H. R. Barton, J. Dorchak, and J. C. Jaszberenyi, The invention of radical reactions. Part XXIV. Relative rates of acylation and radical deoxygenation of secondary alcohols, Tetrahedron, 48 7435 (1992). 

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. 

The products were obtained in excellent yields after simple hexane extraction. The removal of bromine and iodine proceeded smoothly. The removal of PhSe afforded methylcyclohexanone, indicating that the decarbonylation of acyl radicals takes place. The efficiency of deoxygenation of alcohols (Barton-McCombie reaction) is independent of the type of thiocarbonyl derivative (i.e. 0-arylthio-carbonate, O-thioxocarbamate, thiocarbonylimidazole or xanthate), as previously reported for (TMS)3SiH in organic solvents.25... 

Radical deoxygenation of sec.-alcohols, Barton-McCombie reaction.2" This reaction proceeds more rapidly with xanthates [ R CHOC(S)SCHr than with any of the known phenoxy thiocarbonyl derivatives [R2CHOC(S)OCf,H ]. Of these the unsubstituted phenoxythiocarbonyl derivative is slightly more reactive than the 2,4,6-trichloro- or the p-fluorophenyl derivative. The pentafluorophcnyl derivative, R2CHOC(S)OC6F5, is the slowest of all known derivatives. 

Two important reactions were introduced by Barton s group. The radical deoxygenation of secondary alcohols via thiono esters is a selective and mild replacement of hydroxy groups by hydrogen [22-25]. The deoxygenation at 2 -position of adenosine via the thionocarbamate derivative has been chosen as an example (Eq. 6)... 

Barton DHR, Blundell P, Dorchak J, Jang DO, Jaszberenyi J (1991) The invention of radical reactions. Part XXL Simple methods for the radical deoxygenation of primary alcohols. Tetrahedron 47 8969-8984... 

Alcohol Deoxygenation. A limitation of the useful Barton-McCombie procedure for the deoxygenation of alcohols is its application to tertiary alcohols because of difficulties in preparing the required xanthate or other derivatives. A solution to this is to first form a monoester with Oxalyl Chloride and then react the remaining acyl chloride function with the sodium salt (3) (eq 6). In these reactions, although r-butanethiol is suitable as the chain carrier, in some cases 3-ethyl-3-pentanethiol gives superior yields (50-90%). The intermediate tertiary radicals can be trapped by powerful Michael acceptors such as 1,2-dicyanoethylene. 

Since its introduction by Barton and McCombie, the deoxygenation of thionocarbonyl derivatives of alcohols has become an important synthetic reaction and a valuable method for the generation of carbon-centered radicals.3-4 Xanthates, thionobenzotes, thionocarbonyl imidazolides, aryloxy thionocarbonate, N-phenylthionocarbamates and oxalate esters are conveniently deoxygenated with tin or silicon hydrides in boiling benzene or toluene.4-5... 

The reaction of triethylboron with oxygen is a convenient way to generate ethyl radicals at room temperature, or at lower temperatures. These conditions at room temperature in the presence of tributyltin hydride efficiently perform the Barton-McCombie deoxygenation reaction. Recently, we showed that the tin hydride could be replaced by diphenylsilane also at room temperature, for the deoxygenation of secondary alcohols.20 Many different thiocarbonyl derivatives can now be used for the Barton-McCombie reaction. Data were collected for R = Ph, />-F-C6H4, C6F5, C6C13H2 with various substrates (Scheme 2). The yields were excellent for all the secondary... 

In the Barton-McCombie radical deoxygenation reaction the hydroxyl group of an alcohol is replaced with a hydrogen atom. Even hindered secondary and tertiary alcohols may be deoxygenated by this method. In a typical procedure the alcohol is first converted to a thioxoester derivative, which is then exposed to tri-n-butyltin hydride in refluxing toluene. 

The Barton deoxygenation (or Barton-McCombie deoxygenation) is a two-step reaction sequence for the reduction of an alcohol to an alkane. The alcohol is first converted to a methyl xanthate or thioimidazoyl carbamate. Then, the xanthate or ihioimidazoyl carbamate is reduced with a tin hydride reagent under radical conditions to afford the alkane. Trialkylsilanes have also been used as the hydride source. Reviews (a) McCombie, S. W. In Comprehensive Organic Synthesis Trost, B. M. Fleming, I., Eds. Pergamon Press Oxford, U. K., 1991 Vol. 8, Chapter 4.2 Reduction of Saturated Alcohols and Amines to Alkanes, pp. 818-824. (b) Crich, D. Quintero, L. Chem. Rev. 1989, 89, 1413-1432. 

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