Probing electronic effects upon nucleophilicity and Lewis basicity of isothiourea HyperBTM catalyst derivatives

Isothioureas have become a cornerstone of modern Lewis base organocatalysis being involved in a plethora of applications ranging from large scale syntheses to enantioselective reactions to immobilised catalysts. To date, most catalyst structure–activity studies have considered variation of the stereodirecting functionality or chalcogen atom within the catalyst framework. Systematic exploration of substituent electronic effects has been broadly neglected. Herein, the effect of incorporating a range of electron-donating and electron-withdrawing substituents at the 7-, 8-, and 9-positions of the benzannulated part of the HyperBTM scaffold, as well as extended π-systems, is explored. The rate of acylation of a model achiral tertiary alcohol is used to benchmark catalyst reactivity, while catalyst selectivity is evaluated by comparing the effectiveness of secondary and tertiary alcohol acylative kinetic resolutions. The reaction of the developed catalysts with benzhydrylium ions was used to determine their nucleophilicity and Lewis basicity. Comparison of the catalysts indicated that highest reactivity and selectivity was generally observed with the incorporation of electron-donating substituents at the aromatic part of the HyperBTM skeleton, which also correlated with higher nucleophilicity and Lewis basicity.