Tritiodefluorination of alkyl C–F groups

Abstract

A straightforward methodology of fluorine substitution by tritium/deuterium is reported. The described method is selective towards the F─C (sp3) group and leaves both the aromatic F─C (sp2) and F2─C (sp3) moieties unaffected. Alkylfluorides, readily synthesized from appropriate alcohols by treatment with diethylaminosulfur trifluoride (DAST) reagent in an overall yield up to 76%, undergoes activation with the boron‐based Lewis acid B(C6F5)3, and stoichiometric in situ reduction with a tritide/deuteride reagent—the [TMP2(3)H][2(3)HB(C6F5)3] system of frustrated Lewis pair. This methodology provides an isolated yield of up to 93% of regio‐specifically labeled small organic compounds with superior 2H‐enrichment of over 95%. The specific activity of prepared 1‐(2‐[3H]‐ethyl)naphthalene was determined at 29.0 Ci/mmol. The site selectivity of the Lewis acid/ [TMP2(3)H][2(3)HB(C6F5)3] approach is orthogonal to currently used methods and allows for isotopic labeling of complementary positions in molecules. Reported labeling methodology proceeds well at ultra‐mild reaction conditions (220 mbar of T2), allowing very low consumption of the radioactive source (4.2 Ci/156 GBq), and producing limited amount of radioactive waste.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“…Recently, the concept of frustrated Lewis pairs has been shown to enable the deuteration and tritiation of C(sp 3 )−F bonds using deuterium or tritium gas activated by the combination of B(C 6 F 5 ) 3 and TMP (Scheme 78). 248 Under comparably mild and metal-free reaction conditions, aliphatic C−F bonds led to very high deuterium incorporation (>95%) in the presence of aromatic ones while facilitating tritiation under very low pressures of tritium gas. In a more biochemically relevant context, the excited state reactivity of a palladium catalyst was harnessed for the preparation of C2-deuterated 2-deoxy sugars (Scheme 79).…”