Improving the Yield of the Exhaustive Grignard Alkylation of N-Benzylphthalimide

Abstract

The tetraalkylation of N-benzylphthalimide is the major yield limiting step in the common synthetic route to isoindoline nitroxides. The progress of this reaction was found to be limited by the formation of previously unobserved mono- and dialkyl side products that do not lead to the desired product. The yield for the tetraalkylation of N-benzylphthalimide with ethylmagnesium iodide could be increased (60 % over two steps) when a stepwise addition sequence was employed. The new two-step synthesis offers a practical preparative scale alternative to the current approach.

Paramagnetic Chemical Probes for Studying Biological Macromolecules

“…A more efficient procedure than a quadruple Grignard addition was found later, which proceeded via isolation of the monoaddition product (compound 56 ) and subsequent conversion into compound 57 (Scheme ). The further transformation of the benzylamine to a nitroxide was achieved by debenzylation and oxidation (Scheme , 58 ). − The latter compound can readily be transformed into a probe, such as compound 59a/b (Scheme ), which can be attached to a thiol group of a biological macromolecule . Several other routes toward functionalized isoindolinyl nitroxides have been reported.…”

Synthesis of two novel pyridine annulated pyrrolidine nitroxides

“…methylation of imide 13 were revealed (Scheme 6). Previous literature (Jayawardena et al, 2013) (Colwell et al, 2011). Absence of any methyl groups at the fourth position of the pyridine ring of two tetraalkyl adducts (14 or 15) exhibits that intermediate 19a would remain as an inert structure for further Grignard methylation.…”

Advances in the synthesis of nitroxide radicals for use in biomolecule spin labelling

“…This proceeds best when hemiaminal 32 is isolated (from a single addition), and then resubmitted to excess Grignard reagent, giving tetrasubstituted isoindoline 33 in respectable yield. 13,22 Subsequent functional group manipulations and N-oxidation are carried out to afford the isoindoline spin label.…”