Cofactor-mimetic aerobic oxidation has conceptually merged with catalysis of syngas reactions to form a wide range of Markovnikov-selective olefin radical hydrofunctionalizations. We cover the development of the field and review contributions to reaction invention, mechanism and application to complex molecule synthesis. We also provide a mechanistic framework for understanding this compendium of radical reactions.

We report the discovery of an outstanding reductant for metal-catalyzed radical hydrofunctionalization reactions. Observations of unexpected silane solvolysis distributions in the HAT-initiated hydrogenation of alkenes reveal that phenylsilane is not the kinetically preferred reductant in many of these transformations. Instead, isopropoxy(phenyl)silane forms under the reactions conditions, suggesting that alcohols function as important silane ligands to promote the formation of metal hydrides. Study of its reactivity showed that isopropoxy(phenyl)silane is an exceptionally efficient stoichiometric reductant and it is now possible to significantly decrease catalyst loadings, lower reaction temperatures, broaden functional group tolerance and use diverse, aprotic solvents in iron- and manganese-catalyzed hydrofunctionalizations. As representative examples, we have improved the yields and rates of alkene reduction, hydration, hydroamination and conjugate addition. Discovery of this broadly applicable, chemoselective and solvent-versatile reagent should allow an easier interface with existing radical reactions. Finally, isotope-labeling experiments rule out the alternative hypothesis of hydrogen atom transfer from a redox-active beta-diketonate ligand in the HAT step. Instead, initial HAT from a metal-hydride to directly generate a carbon-centered radical appears to be the most reasonable hypothesis.

Hydrogen atom transfer (HAT) circumvents a disfavored Friedel-Crafts reaction in the derivatization of the inexpensive monoterpene isopulegol. A variety of readily-prepared aryl and heteroaryl sulfonates undergo a formal hydroarylation to form 8-arylmenthols, privileged scaffolds for asymmetric synthesis, as typified by 8-phenylmenthol. High stereoselectivity is observed in related systems. This use of HAT significantly extends the chiral pool from the inexpensive monoterpene isopulegol.

Review: 476 refs.

Lindenane oligomers isolated from Chloranthus pose significant challenges for chemical synthesis. The structure of a proposed biosynthetic monomer, lindenatriene, was recently called into question. Its attempted synthesis produced a compound whose 1 H NMR spectrum differed significantly from the spectrum of a monomer produced by oligomer pyrolysis. Here we propose that the original structural assignment after pyrolysis was correct and instead the spectra of synthetic materials were misinterpreted. Reanalysis of 2D NMR data suggest that lindenatriene isomerizes (formal [1,7]-hydrogen shift) upon treatment with base.