The Xanthate Route to Ketones: When the Radical Is Better than the Enolate

The alkylation of enolates is one of the backbones of ketone chemistry, yet in practice it suffers from numerous limitations due to problems of regiochemistry (including O- versus C-alkylation), multiple alkylations, self-condensation, competing elimination, and incompatibility with many polar groups that have to be protected. Over the years, various solutions have been devised to overcome these difficulties, such as the employment of auxiliary ester or sulfone groups to modify the pKa of the enolizable hydrogens, the passage by the corresponding hydrazones, the use of transition-metal-catalyzed redox systems to formally alkylate ketones with alcohols, etc. Most of these hurdles disappear upon switching to alpha-ketonyl radicals. Radicals are tolerant of most polar functions, and radical additions to flat sp(2) centers are generally easier to accomplish than enolate substitution at tetrahedral sp(3) carbons. The main stumbling block, however, has been a lack of generally applicable methods for the generation and intermolecular capture of alpha-ketonyl radicals. We have found over the past years that the degenerative exchange of xanthates represents in many ways an ideal solution to this problem. It overcomes essentially all of the difficulties faced by other radical processes because of its unique ability to reversibly store reactive radicals in a dormant, nonreactive form. The lifetime of the radicals can therefore be significantly enhanced, even in the concentrated medium needed for bimolecular additions, while at the same time regulating their absolute and relative concentrations. The ability to perform intermolecular additions to highly functionalized alkene partners opens up numerous possibilities for rapid and convergent access to complex structures. Of particular importance is the elaboration of ketones that are prone to self-condensation, such trifluoroacetone, and of base-sensitive ketones, such as chloro- and dichloroacetone, since the products can be used for the synthesis of a myriad fluorinated and heteroaromatic compounds of relevance to medicinal chemistry and agrochemistry. The formal distal dialkylation of ketones, also of utmost synthetic interest, is readily accomplished, allowing convenient access to a wide array of useful ketone building blocks. Cascade processes can be implemented and, in alliance with powerful classical reactions (aldol, alkylative Birch reductions, etc.), furnish a quick route to complex polycyclic scaffolds. Furthermore, the presence of the xanthate group in the adducts can be exploited to obtain a variety of arenes and heteroarenes, such as pyrroles, thiophenes, naphthalenes, and pyridines, as well as enones, dienes, and cyclopropanes. Last but not least, the reagents and most of the starting materials are exceedingly cheap, and the reactions are safe and easy to scale up.