Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines

Sergey Pronin, Christopher Reiher, and Ryan Shenvi
DOI: 10.1038/nature12472


The bimolecular nucleophilic substitution (SN2) reaction is a well understood and widely used chemical transformation that allows a chemist to affect useful functional group interconversions or combine two molecules. A significant advantage of the SN2 reaction over the related (and often competitive) unimolecular nucleophilic substitution (SN1) reaction is that it provides predictable stereoinversion at the electrophilic carbon centre. SN2 processes do, however, suffer from a significant limitation: intolerance of tertiary electrophilic carbon atoms, where steric crowding inhibits the approach of the nucleophilic reacting partner. This drawback limits the stereochemical complexity of possible reaction substrates and the utility of nucleophilic substitution in the synthesis of challenging chiral molecules.

Now, a team of researchers from California led by Ryan Shenvi have developed a process that allows the stereochemical inversion of tertiary alcohols with nitrogen-based nucleophiles. The key reaction in their discover y involves Lewis-acid-catalyzed solvolysisof a tertiary alcohol derivative – trifluoroacetate or perfluoroalkanoate esters — in the presence of excess trimethylsilyl cyanide. Addition of the cyanide nucleophile to the carbocation of a postulated contact ion pair, generated by solvolysis, occurs with high enantioselectivity, giving tertiary isonitrile products in a remarkably simple transformation. The researchers compare this process to proposed biosynthetic pathways of nitrogen-based marine terpenoids, which are known to derive from the addition of inorganic cyanide to highly substituted carbon centres.


As well as extending the scope of traditional SN2 processes, Lewis-acid-catalyzed solvolysis also provides complementary reactivity. Because the reaction is conceptually related to the SN1 reaction in the generation of a reactive carbocation in the contact ion pair, activated primary and secondary alcohols do not undergo solvolysis even over extended reaction times. The utility of the process was further demonstrated by converting the isonitrile products into various useful nitrogen-based compounds, such as amines, formamides and isothiocyanates.

The influence of steric crowding on this SN2-like reaction has not, however, been eliminated; branched tertiary alcohols react with lower stereoselectivity than minimally substituted analogues. Despite this, the reported transformation fills a gap in modern synthetic methodology and may lead to further developments in the synthesis of other stereo-defined tertiary-substituted compounds.


2 thoughts on “Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines

  1. joaquinbarroso

    It would be interesting (haven’t read the paper, sorry) to try this reaction in a highly coordinating solvent to find out to what extent the contact pair is conserved. So many variables to be explored *sigh* makes me miss my times in the (real) lab.

    1. paulm Post author

      Well, the reaction is carried out with TMSCN as the solvent (and reagent). The authors do briefly discuss attempting the reaction using other nucleophiles/solvents without success. I get the impression that the reaction (unsurprisingly) is a delicate balance.


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