SYNTHESIS OF VERY HIGH SPECIFIC ACTIVITY N TRITIOACETOXYPHTHALIMIDE: TRITIUM NMR

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The usefulness of N-tritioacetoxyphthalimide as an efficient acetylation reagent encouraged us to investigate methods to increase the isotopic content of the methyl group. An appropriate precursor is dichloroacetic acid which can be deuteriodehalogenated with D2 gas and Pd/Al2O3 in a sodium hydroxide solution. The filtered acetate salt is then acidified and the acetic acid extracted with ether. Addition of N-hydroxyphthalimide in THF, then DCC in methylene chloride produces N-deuterioacetoxyphthalimide in 42% yield with 2.3 deuterium atoms per molecule. Several problems associated with this method remain to be resolved: 1. Formation of the free acid from the salt (acidification). The pH must be between 4 and 5 to avoid exchange, and therefore loss of label. 2. Ease and efficiency of coupling with N-Hydroxyphthalimide - high efficiency coupling in DCC requires a dry ethereal solution.