RADICAL INDUCED DEAMINATION OF PRIMARY & SECONDARY AMINES BY TRIBUTYLTIN TRITIDE

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Primary, secondary, and tertiary aliphatic or alicyclic isocyanides, isothiocyanates and isoselenocyanates are smoothly and selectively reduced under free radical reaction conditions to the corresponding hydrocarbons using TBTH as a reducing agent. These radical reactions can be performed under neutral conditions without the possibility of structural rearrangements. The reaction is conceptually similar to the deoxygenation of primary and secondary alcohols (Barton reaction), and the selective replacement of a primary amino function by a hydrogen atom is a desirable reaction for the labelling of many natural products. Since radical-induced deamination of isocyanides by TBTH is a general reaction of considerable value, the availability of highly labelled TBTT means that this procedure can be developed as a tritium labelling technique. Synthesis of isocyanide substrates for the radical tritiation reaction requires formylation of the amino function using acetic formic anhydride or p-nitrophenyl formate followed by dehydration with phosphorus oxychloride/triethylamine in methylene dichloride to provide the precursor in good yield. For hydroxylated compounds, formylation of the amino group is followed by O-peracetylation with acetic anhydride. It is reported that isothiocyanates are first reduced to isocyanides before deamination, and have little advantage over the isocyanide route. However, isothiocyanates are formed at higher chemical yields than secondary and tertiary isocyanides, and may therefore be advantageous in limited cases. Reaction of isocyanides with TBTH requires the presence of AIBN as initiator, and heat, and the relative ease of reduction is tertiary > secondary > primary. Aromatic isocyanides are not reduced under these reaction conditions. We have applied this approach to the synthesis of 2-deoxyglucose and used glucoseamine as the starting material. Glucoseamine was liberated from the hydrochride salt and then was N-formylated. The N-formylglucoseamine was peracetylated, and the product was dehydrated to give 2-glucoseamine isocyanide, which was then isolated and purified for the labelling reaction. Cyanide abstraction was achieved with freshly made tributyltin deuteride in benzene at 80oC for 2 hours in the presence of a catalytic amount of AIBN. The product tetra-O-acetyl-[2-2H]-deoxyglucose was analysed with 1H/2H NMR spectroscopy to show deuterium peaks at 1.5 and 2 ppm. Subsequent deacetylation in the final step generated [2-2H]-deoxyglucose. An analogous application of n-tributyltin tritide (25% tritium) to the synthesis of 2-tritio-2-deoxyglucose did not give the product, and the starting material was recovered. The reaction is under further investigation with deuterium before repetition of the tritium labelling experiment.