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| Barton–McCombie deoxygenation | |
|---|---|
| Name | Barton–McCombie deoxygenation |
| Type | Organic redox reaction |
| Namedafter | Sir Derek Barton; W. S. McCombie |
Barton–McCombie deoxygenation is an organic transformation that converts oxygenated functional groups into hydrocarbons by replacing alcohol-derived oxygen substituents with hydrogen. Developed in the context of mid-20th century synthetic organic chemistry, this radical-mediated protocol enabled streamlined access to deoxygenated frameworks used in total synthesis campaigns by practitioners linked to institutions such as University of Oxford, University of Glasgow, and industrial laboratories like DuPont.
The reaction uses a radical chain process to remove oxygen atoms from oxygenated substrates by way of sulfur-centered intermediates, typically employing thiocarbonyl derivatives and radical initiators. It is prominent alongside other deoxygenation techniques developed by researchers at Harvard University, Massachusetts Institute of Technology, and California Institute of Technology during the postwar expansion of synthetic methodology. Chemists from groups led by E. J. Corey and Robert B. Woodward incorporated the transformation into complex molecule syntheses, linking it to the broader tradition of strategic bond disconnections in retrosynthetic analysis.
The mechanism proceeds by conversion of an alcohol to a thiocarbonyl derivative such as a thiocarbonylimidazolide, xanthate, or thiocarbonylthioester, followed by radical generation. Initiation often uses organotin hydrides (e.g., tributyltin hydride) with radical initiators such as azobis(isobutyronitrile) associated with researchers at University of Cambridge and Princeton University. A hydrogen-atom transfer from the stannane to a carbon-centered radical yields the deoxygenated product, while tin-centered radicals propagate the chain. Alternative initiators and mediators introduced by groups at ETH Zurich and University of California, Berkeley modify propagation and termination steps. The mechanism shares conceptual features with radical reductions utilized by groups including Kitasato University and University of Tokyo.
The transformation applies to primary, secondary, and tertiary alcohols after conversion to appropriate thiocarbonyl derivatives, and it has been used in syntheses of natural products by teams at Scripps Research Institute, Columbia University, and Stanford University. It is particularly valuable when other deoxygenation strategies from laboratories like Max Planck Institute or Institut Pasteur are incompatible with sensitive functional groups, and it features in total syntheses by chemists such as E. J. Corey, Phil S. Baran, and K. C. Nicolaou. Applications extend to steroid modifications, terpene skeleton manipulations, and late-stage functionalization campaigns in pharmaceutical research at GlaxoSmithKline, Pfizer, and Roche.
Typical procedures begin with preparation of a xanthate or thiocarbonylimidazolide from the alcohol using reagents developed in laboratories at Imperial College London and University of Manchester. The deoxygenation step commonly employs tributyltin hydride under inert atmosphere with thermal initiators or photochemical activation pioneered at California Institute of Technology. Reaction temperatures vary from ambient to refluxing solvents such as benzene or toluene used historically in work at University of Illinois Urbana-Champaign. Modern adaptations replace organotin hydrides with alternatives like tris(trimethylsilyl)silane developed by researchers at University of Tokyo and photoredox catalysts investigated at University of California, Los Angeles. Workup typically requires careful removal of metal residues, a concern addressed in studies from ETH Zurich and industrial protocols at BASF.
Numerous variants adapt the core radical deoxygenation to improve safety, selectivity, and environmental profiles. Organosilane hydrides from Tohoku University and photoredox-catalyzed single-electron transfer methods reported from Massachusetts Institute of Technology and University of Edinburgh allow tin-free protocols. Electrochemical approaches explored at University of Oxford and CNRS enable anodic or cathodic initiation of radical chains. Radical chain carriers and hydrogen atom donors studied by groups at Yale University and University of Michigan broaden substrate compatibility. Xanthate transfer and Barton ester alternatives introduced by investigators linked to Tokyo Institute of Technology complement the original toolkit.
Limitations include toxicity and removal of organotin byproducts, a concern noted by regulatory bodies and researchers at Health Canada and European Medicines Agency. Competitive reduction, over-reduction, or fragmentation can occur with substrates bearing β-scission-prone motifs; such outcomes were documented in syntheses from Columbia University and University of California, San Diego. Radical addition to alkenes and undesired rearrangements have been reported in case studies from University of Wisconsin–Madison and Princeton University. Steric hindrance can impede radical formation or hydrogen-atom transfer, demanding modified conditions developed by teams at University of Texas at Austin and Northwestern University.
The method is historically rooted in work by Sir Derek Barton and co-workers whose research programs intersected with contemporaries at University of Oxford and industrial chemistry groups. Subsequent elaborations and practical improvements were advanced by W. S. McCombie and investigators at institutions including University of Glasgow, Scripps Research Institute, and Imperial College London. Later contributions from laboratories led by K. C. Nicolaou, E. J. Corey, and Phil S. Baran integrated the deoxygenation into complex syntheses and developed safer, more general variants, while methodological diversification continued across academic and industrial settings such as Max Planck Institute and Pfizer.
Category:Organic reactions