Tag Archives: Nucleophilic addition

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.

Facile Preparation of Indoles and 1,2-Benzothiazine 1,1-Dioxides

Masahito Yamagishi, Ken Nishigai, Azusa Ishii, Takeshi Hata and Hirokazu Urabe Angew. Chem. Int. Ed.
DOI: 10.1002/anie.201201024

The addition of nucleophiles into electron deficient π-systems is a powerful and widely used concept in synthesis. Urabe and co-workers have shown that bromoalkynes can behave as competent electrophiles for such additions and demonstrate how the unique products of sulfonamide addition can act as precursors for heterocycle synthesis.

Addition under basic conditions with heating results in isolation of the cis-enamine as the only observed product. With an aryl substituent on the nitrogen, the adduct undergoes cyclisation by palladium catalysis to give the indole product. This process can be applied in a one-pot procedure, giving the indole scaffold in one step.

When an arylsulfonamide nucleophile does not contain an N-aryl substituent, an alternative heterocyclic system can be isolated from subjecting the addition product to palladium catalysis. 1,1-dioxobenzothiazines can be prepared using a 10 mol% loading of palladium acetate.

The higher catalyst loading is required for the less favourable cyclisation. When an N-aryl arylsulfonamide is subjected to cyclisation conditions only the indole product is observed.