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Paper | Regular issue | Vol 32, No. 12, 1991, pp.2343-2355
Published online, 1st January, 1970
DOI: 10.3987/COM-91-5831
A Practical Synthesis of Isotopically Labelled 1-(4-Isothiocyanatophenyl)-4-(t-butyl)-2,6,7-trioxabicyclo[2.2.2]octane, a Probe for the Benzodiazepine Receptor Coupled Chloride Ionophore

Brian R. de Costa, Anita Lewin, Joyce A. Schoenheimer, Phil Skolnick, and Kenner C. Rice*

*Building 8, Room B1-23, Laboratory of Medicinal Chemistry, National Institutes of , Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, U.S.A.


An efficient synthesis of high specific activity [3H]1-(4-isothiocyanato-3,5-ditritiophenyl)-4-(t-butyl)-2,6,7-trioxabicyclo[2.2.]octane ([3H]-1), an affinity ligand for the benzodiazepine (BZ)-coupled γ-aminobutyric acid (GABA)-gated chloride channel, was achieved starting with methyl p-aminobenzoate and 3-(t-butyl)-3-oxetanemethanol. A key step in the reaction sequence utilized the azide group as a latent aromatic amine allowing synthesis of 1-(4-amino-3,5-ditritiophenyl)-4-(t-butyl)-2,6,7-trioxabicyclo[2.2.2]octane ([3H]-18) via boron trifluoride etherate catalysed isomerization of 3-(t-butyl)-3-(3,5-dibromo-4-azidobenzoyloxymethyl)oxetane (15) to 1-(3,5-dibromo-4-azidophenyl)-4-(t-butyl)-2,6,7-trioxabicyclo[2.2.2]octane (17). Model experiments performed in an attempt to use unprotected or trifluoroacetamide protected aromatic amines in this sequence of reactions were unsuccessful.