It’s turnabout time for triply substituted alcohols in a new reaction, which flips the configuration of the alcohols’ central carbon as the compound is transformed into an isonitrile. The reaction provides a shortcut to compounds with tertiary alkylisonitriles or tertiary alkylamines that could make it easier to synthesize natural products and design new pharmaceuticals and materials.

Students of organic chemistry learn early that the S_N2 reaction—in which a nucleophile displaces a leaving group in such a way that the substrate’s stereochemical arrangement is flipped—can’t take place on tertiary carbons. The triply-substituted carbon electrophile is simply too crowded for the reaction’s required backside attack.

Now chemists have come up with an S_N2-like reaction that transforms tertiary alcohols into tertiary alkylisonitriles while inverting the substrate’s stereochemistry (Nature 2013, DOI: 10.1038/nature12472). Ryan A. Shenvi, Sergey V. Pronin, and Christopher A. Reiher of Scripps Research Institute, in La Jolla, Calif., developed the reaction, which makes use of the strong Lewis acid scandium(III) trifluoromethanesulfonate. The substrate alcohols are converted into trifluoro-acetate esters, which undergo attack by the nucleophile trimethylsilyl cyanide. The resulting isonitrile can be converted into many other nitrogen-containing functional groups, Shenvi noted.

The work was also presented this week at the ACS national meeting in Indianapolis in a symposium held by the Division of Organic Chemistry.

Shenvi told C&EN that he wouldn’t call the transformation an S_N2 reaction because about 10% of the product retains its original stereochemical configuration. “That might indicate that the reaction doesn’t proceed through a single transition state,” he said. Rather, Shenvi suspects the reaction forms a transient ion pair that blocks the incoming nucleophile from one side of the substrate.

“The stereocontrolled synthesis of aliphatic amines remains a challenging endeavor, and Shenvi’s work not only provides an excellent solution but does so in a functional-group-tolerant manner with readily accessible reagents and intermediates,” commented John L. Wood, an expert in organic synthesis at Baylor University, in Texas. “There are certainly many methods that one can employ to access these compounds, but none that are as direct.”

Shenvi’s team is currently using the reaction to make antimalarial compounds, but he has bigger plans. “The way forward is to develop an entire arsenal of S_N2-like reactions of tertiary alcohols that don’t incorporate just nitrogen” but sulfur, oxygen, and carbon as well, he said.