Barton and McCombie

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]. 

This procedure Illustrates a simple, general method for the rieoxygenation of secondary hydroxyl groups. It is particularly useful for reducing hindered alcohols. The method was first described hy Barton and McCombie who have reviewed a number of other examples. ... 

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 original conception of Barton and McCombie [10], which is summarized in Scheme 2, was later questioned [15], The alternative mechanism summarized in Scheme 4 was suggested. However, a low-temperature study using the nuclear magnetic resonance (NMR) of ll9Sn confirmed the original proposal [10], The evidence for the correctness of Scheme 2 is summarized in several communications [16-20] so that further discussion is not needed. 

The method is a modification of one used by Barton and McCombie.8 Reduction of ketones.9 Ketones can be reduced to alcohols by Bu3SnH in the presence of either AIBN or a Lewis acid, but this reaction is limited to unhindered ketones. However, even sterically hindered ketones, such as f-butyl methyl ketone, can be reduced under high pressure (10 kbar) in the absence of a catalyst. This method is particularly useful in the case of cyclopropyl and a,p-epoxy ketones, which are reduced to the corresponding alcohols. Reduction of these ketones with Bu3SnH under radical conditions results in ring-opened products. 

For the preparation of a 3 -deoxy Lex analogue, an acylated 3-deoxy-D-. v/o-hexopyranose was used. The latter was prepared either from phenyl 1-thio-D-galactopyranoside78 or from l,2 5,6-di-0-isopropylidene-a-D-galactofuranose,79 via the Barton and McCombie deoxygenation method. 

One approach started from partially protected rhamnosyl derivatives. Thus, from easily obtained 2,3-<3-isopropylidene-a-L-rhamnopyranoside, deoxygenation at C-4 by the Barton and McCombie procedure afforded the 4,6-dideoxy-a-L-/yxo-hexopyranoside derivative.234... 

Deoxygenation of RiCHOH1 (11, 550). Radical deoxygenation of secondary alcohols via thiocarbonyl esters was introduced by Barton and McCombie. More recently, phenoxythiocarbonyl esters have been recommended for the radical deoxygenation (10, 306-307). Particularly rapid and quantitative reduction can be obtained using 2,4,6-trichlorophenoxy- or pentafluorophenoxythiocarbonyl esters. 

Fig. 1.39. Reduction of an alcohol by means of the radical substitution reaction of Barton and McCombie. In terms of Figure 1.2 a "substitution including a fragmentation" occurs.

Defunctionalization of an alcohol by means of the radical substitution reaction of Barton and McCombie. 

For a given secondary alcohol, the choice of thiocarbonyl derivative is predicated more by structural features (steric hindrance, other functional groups) present in the alcohol than by the actual reductive step. Barton and McCombie reported comparable results for 5-methyldithiocarbonyl (MDC), thioben-zoyl (TB) and imidazole-1-thiocarbonyl (ITC) derivatives, and typical preparations of these are shown in... 

Additionally, the reduction process of Barton and McCombie has been developed into a useful technology. The Barton-McCombie procedure (Scheme 8.22) involves the conversion of an alcohol to a thiocarbonate (or dithiocarbonate) derivative (usually in two steps) and the reaction of the latter with tributyltin hydride and azobisisobutyronitrile (AIBN) (bis(l-cyano-l-methylethyl)diazine, [(CH3)2C(CN)N=NC(CN)C(CH3)2]). As shown in Scheme 8.22, decomposition of AIBN produces a radical, which, in turn, abstracts hydrogen from tributyltin hydride, generating the tributyltin radical. The reaction of the latter with sulfur and the subsequent decomposition of that intermediate produces a deoxygenated. 

In their seminal paper, Barton and McCombie describe a method to deoxygenate secondary alcohols through a radical chain mechanism. This process was presented as an alternative to the standard conditions of derivatization of an alcohol to a tosylate/mesylate followed by reduction. Such polar processes are problematic with hindered carbon centers and can lead to rearrangements and/or eliminations if carbocationic intermediates are involved. 

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