Catalyst-Controlled, Selective Functionalization of Conjugated Dienes with Sulfur Imide Reagents

Organic transformations to install heteroatoms continue to be a thriving area of research for synthetic chemists. The synthesis of small, heteroatom-containing molecules from inexpensive and abundant starting materials, such as hydrocarbons, requires unique methods that provide activation of the hydrocarbon without affecting the substrate scope and/or disturbing the reactivity of the heteroatom source. Efforts to accomplish these tasks are discussed. Emphasis is placed on the hetero-Diels-Alder reaction of sulfur imide dienophiles. Sulfur imide reagents are highly electrophilic sources of sulfur and nitrogen. Exploiting the distinctive properties of sulfur, together with the sulfur-nitrogen bond, a method to access 1,4-aminothiols has been developed. This difunctionalization strategy installs two diverse functional groups in a selective manner across 1,3-dienes. Whereas traditional methods to install a single heteroatomic functional group suffer from regiocontrol alone. The developed method for 1,4-aminothiolation must provide both regio- and diastereocontrol. Owing to the inclusion of a concerted [4+2]-cycloaddition as the first step in a tandem process, the aminothiolation protocol established within is able to achieve complete regio- and diastereocontrol. This method represents the first concise, direct method to access aminothiol scaffolds from abundant 1,3- dienes. Additionally, the mechanistic investigation suggests the transformation proceeds through a highly reactive [10-S-4] sulfurane, generated via nucleophilic addition of a Grignard reagent. Notably, the second step of this tandem process is not able to provide the desired aminothiol functionality without the addition of Lewis acid. Subsequent the presence of a copper catalyst in the tandem process to generate aminothiols from 1,3-dienes, the development of a chiral Lewis acid catalyst was studied. With the advent of a chiral Lewis acid catalyst, an asymmetric hetero-Diels-Alder reaction may be developed to provide enantioenriched [4+2] adducts. The utility of [4+2] adducts of sulfur imide reagents extends beyond the scope of the aminothiolation protocol. With proper selection of a sulfur imide reagent it may be possible to access products of aminothiolation, aminoarylation, amination, and others. In the presence of a chiral SnCl4•(R)-SITCP catalyst, a homoallylic amination was achieved in up to 61% enantiomeric excess.