Jimmy Wu, a chemistry professor at Dartmouth, recently published an article in the Journal of the American Chemical Society (J.A.C.S).  Wu’s lab focuses on the formation of carbon-sulfur (C-S) bonds both as precursors for the formation of carbon-carbon bonds, and as precursors for “biologically relevant molecules,” Wu said.

In this article, they discuss finding a method of regioselective control over adding hard nucleophiles in the allylic position of a given substrate/molecule.  Wu’s lab has found that, in the presence of a copper catalyst, they are able to achieve over 95 percent specificity for addition to the alpha position over the gamma position (see Fig. 1).  The leaving groups found to work well in these substitution reactions were phosphorothioate groups, phosphate derivatives bridged to a carbon by a sulfur atom.

Fig. 1: Specificity of nucleophilic addition can be obtained using a catalyst

With the exception of CuCN, many different copper catalysts used in reactions with Grignard reagents (R-MgCl, where R represents several different possible hydrocarbon groups) showed 87% specificity for a allylic substitution over g substitution, and 95% specificity for forming an E alkene over a Z alkene.  The reaction of isopropyl-MgCl with a copper (II) thiocyanate (CuSCN) catalyst resulted in 95% selection for a over g substitution.

The proposed mechanism, as shown in Fig. 2 explains how copper is able to do this with such high specificity.  The copper catalyst coordinates with the hard nucleophile (carbanions from the Grignard reagents, specifically), and then the allylic complex attaches as a ligand to the copper as the phosphothioate leaving group comes off.  Then, the copper transfers the nucleophile to form either a or g substituted compounds.

 

Fig. 2: The Copper-catalyzed mechanism

In addition to regiospecificty (where on a molecule the nucleophile adds), Wu’s lab also looked at the stereospecificity (related to orientation of the substituents bound to a carbon in space) of these reactions.  It was shown that, with enantioenriched mixtures of the allylic substrate, addition of the nucleophile predominantly led to inversion of stereochemistry.  Though the mechanism illustrated in Fig. 2 is far from a simple SN­2 substitution, there is still consistent inversion of stereochemistry at the point of the initial C-S bond in the substrate.

Wu said that his lab plans to study what happens to the leaving group once it falls off from the allylic position. In particular, they would like to determine if it coordinates with the copper and how such an interaction could affect the copper’s functionality.

References:

1. A. M. Lauer, F. Mahmud, J. Wu. J. Am. Chem. Soc. 133(23): 9119-9123 (2011). Available online at http://pubs.acs.org/doi/abs/10.1021/ja202954b.