Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: a stereo- and regio- selective study

The reactions of enantiopure cyclohexene epoxides and trans‐1,2‐bromoacetates, derived from the corresponding substituted benzene cis‐dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2‐aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans‐1,2‐azidohydrins were prepared by Lewis acid‐catalysed ring‐opening of cyclic vinyl epoxides with sodium azide via an SN2 mechanism. On heating, these trans‐1,2‐azidohydrins isomerized to the corresponding trans‐1,4‐azidohydrins via a suprafacial allyl azide [3,3]‐sigmatropic rearrangement mechanism. Conversion of a 1,2‐azidohydrin to a 1,2‐azidoacetate moved the equilibrium position in favour of the 1,4‐substitution product. Allylic trans‐1,2‐bromoacetates reacted with sodium azide at room temperature to give C‐2 and C‐4 substituted products. A clean inversion of configuration at C‐2 was found, as expected, from a concerted SN2‐pathway. However, substitution at C‐4 was not stereoselective and resulted in mixtures of 1,4‐cis and 1,4‐trans products. This observation can be rationalized in terms of competitive SN2 and SN2′ reactions allied to a [3,3]‐sigmatropic rearrangement. cis‐1,2‐Azidohydrins and cis‐1,2‐azidoacetates were much more prone to rearrange than the corresponding trans‐isomers. Reaction of the softer tosamide nucleophile with trans‐1,2‐bromoacetates resulted, predominantly, in C‐4 substitution via a syn‐SN2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans‐1,2‐aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an SN2 mechanism. Copyright © 2013 John Wiley & Sons, Ltd. Multiple reaction pathways including SN2, SN2′, and [3,3]‐sigmatropic rearrangement mechanisms are required to rationalize the formation of products obtained from the reaction of cyclohexene epoxides and trans‐bromoacetates with azide and other nitrogen nucleophiles.