Hydrogen Bond Activation of Donor Acceptor Cyclopropanes
Abstract
Donor acceptor cyclopropanes (DACs) are versatile organic building blocks used in the synthesis of many pharmaceutically relevant heterocycles. The combination of a high ring strain cyclopropane core and vicinal donor and acceptor substituents cause DACs to behave like 1,3-zwitterions. Recently, DACs have been activated by a hydrogen bond donor solvent in place of a Lewis acid catalyst, allowing the elimination of heavy metals commonly used in these transformations. Hexafluoroisopropanol (HFIP) as a hydrogen bond donor cosolvent was found to cause a downfield shift of the DACs electrophilic carbon in the 13C NMR spectrum. This indicates increased electrophilicity at this position (Structure A vs B). NMR spectroscopy titrations were used to study the host-guest interaction between DACs and HFIP. The data collected was compared to the effects of binding a Lewis acid catalyst such as scandium triflate (Sc(OTf)3). The HFIP conditions used previously by the Kerr group caused a further downfield shift than commonly used catalytic amounts of scandium triflate. To further expand the application of the HFIP method, the ring-opening addition reaction of DACs with thiol nucleophiles is reported here. Yields were comparable or slightly improved when compared to similar transformations that used a metal-based catalyst. Electron donating and withdrawing properties of the thiol reagents had very strong effects on the results, resulting in two sets of conditions for this methodology.