Further Insights into the Exhaustive Grignard Tetramethylation of N-benzylphthalimide.

1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) is one of the most versatile isoindoline nitroxides due to the applications and a variety of important advantages it possesses. TMIO had been prepared previously by few different approaches, but none of these produced good yields due to the involvement of higher number of steps in the synthetic pathway. The most common pathway used to prepare TMIO involves the treatment of N-benzylphthalimide with methylmagnesium halide (MeMgX), followed by deprotection and oxidation. This Grignard approach remains the most effective when it comes to the synthesis of TMIO due to the higher overall yield obtained (36%) and the involvement of only four steps. However, the major yield limiting step in this route is the reaction between N-benzylphthalimide and MeMgX. The limited yield of this step is a mystery for 40 years due to some unknown reasons. Therefore, the author had decided to mechanistically investigate the aforesaid reaction with the aim of searching the reasons that lead to the limited yield. Analysis of the Grignard reaction mixture through a novel aqueous work-up (that was different to published Griffiths’ work-up) demonstrates the formation of five products including the target, N-benzyl-1,1,3,3-tetramethylisoindoline. Two of them among five products are recognized to be dead-end, while other two did not involve in improving the yield of the target although they both appear to be intermediates on the pathway to form the target. According to the findings of this study, it is finally concluded that a range of potential reactions and the formation of numerous side products could be the possible reasons for the low yield of the Grignard step. [ABSTRACT FROM AUTHOR]