Barton-McCombie Radical Deoxygenation Reaction

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. 

In the asymmetric synthesis of the C1-C19 fragment of kabiramide C, to complete the stereochemical array, J. Panek and co-workers used, among other methods, the Barton-McCombie deoxygenation protocol.  

Danishefsky and co-workers developed a synthetic route to the neurotrophic illicinones and a total synthesis of the natural product tricycloillicinone. Illicinones were found to enhance the action of choline acetyltransferase, which catalyzes the synthesis of acetylcholine from its precursors. The application of Corey-Snider oxidative cycHzation and the Barton-McCombie radical deoxygenation provided a direct route to tricycloillicinone. 

In the laboratory of V. Singh a novel and efficient stereospecific synthesis of the marine natural product capnellene from p-cresol was developed. After rapidly assembling the desired carbon framework, it was necessary to remove the carbonyl group from the tricyclic intermediate which was accomplished using Barton s deoxygenation procedure. 

Luzzio and co-workers devised a total synthesis for both antipodes of the (-)-Kishi iactam, which is a versatiie intermediate for the synthesis of the perhydrohistrionicotoxin (pHTX) aikaioids. in the final stages of the synthesis of the (-)-Kishi lactam, it was necessary to remove one of the secondary alcohol groups. The Barton radical deoxygenation protocol was utilized for this operation. 

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D. Crich, On the use of S-(4-alkenyI)-dithiocarbonates as mechanistic probes in the Barton-McCombie radical deoxygenation reaction, Tetrahedron Lett. 29 5805 (1988). 

The toxicity of organotin derivatives and the difficulty in removing tin residues has spurred considerable eflforts to devise catalytic systems or, preferably, completely tin-free processes for conducting radical reactions. The use of poly(methylhydrosiloxane) in conjunction with a small amount of hexabutylditin oxide, a combination of reagents initially proposed by Grady and Kuivila [21a], has recently been applied to Barton-McCombie type deoxygenations [21b]. Several silanes have been examined... 

The reduction of thiocarbonyl derivatives by EtsSiH can be described as a chain process under forced conditions (Reaction 4.50) [89,90]. Indeed, in Reaction (4.51) for example, the reduction of phenyl thiocarbonate in EtsSiD as the solvent needed 1 equiv of dibenzoyl peroxide as initiator at 110 °C, and afforded the desired product in 91 % yield, where the deuterium incorporation was only 48% [90]. Nevertheless, there are some interesting applications for these less reactive silanes in radical chain reactions. For example, this method was used as an efficient deoxygenation step (Reaction 4.52) in the synthesis of 4,4-difluoroglutamine [91]. 1,2-Diols can also be transformed into olefins using the Barton-McCombie methodology. Reaction (4.53) shows the olefination procedure of a bis-xanthate using EtsSiH [89]. 

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]. 

An interesting neophyl-type radical rearrangement process has been established for the synthesis of azabicycles, which are not readily accessible by other means. Barton McCombie deoxygenation of xanthate 70 under slow addition of (TMS)3SiH and AIBN in refluxing toluene furnished the 2-azabenzonorbor-nane derivative in good yield (Reaction 7.72) [82]. 

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 Barton-McCombie deoxygenation reaction was invented for use in the manipulation of aminoglycoside antibiotics. It has become a popular method because of the mild conditions employed. Radical reactions have advantages over ionic reactions for carbohydrate chemistry. In this context, there is little neighboring group interference in cationic reactions and little elimination compared with normal nucleophilic displacement reactions. 

The initiation of the Barton Decarboxylation ( Bu3Sn-H -> Bu3Sn-) is effected with a radical initiator, and as with the Barton-McCombie Deoxygenation, the driving force for the reaction itself is the formation of the stable S-Sn bond. 

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. 

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... 

Tin hydride 2 prepared from hydroxyl acid behaves like the conventional Bu3SnH in standard free-radical reactions, but the tin-containing by-products are easily removed by mild hydrolysis which converts them into base-soluble materials. The performance of these tin hydrides is evaluated for a range of radical reactions involving halides, selenides, Barton-McCombie deoxygenation, and enyne cyclizations.72... 

The use of polymer-supported tin hydrides is now a well-estabhshed method for minimizing tin contamination in products resulting from radical reactions. A new version of the Barton-McCombie deoxygenation reaction has been developed by Dumartin [4] which combines the use of a polymer-supported tin hydride with a stoichiometric silane reductant, giving an attractive catalytic process. 

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