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 azobisisobutyronitrile (AIBN) as initiator, and heat, and the relative ease of reduction is tertiary > secondary > primary. Aromatic isocyanides are not reduced under these reaction conditions. TITLE: Radical-Induced Deamination of Primary and Secondary Amines by Tributyltin Tritide (Continued) We have applied this technique to the synthesis of 2-deoxyglucose and used glucosamine as the starting material. Glucosamine was liberated from the hydrochloride salt to free amine, and then was N-formylated. The N-formylglucosamine was peracetylated with acetic anhydride and the product was dehydrated to give 2-glucosamine isocyanide, which was isolated and purified for the labelling reaction. Cyanide abstraction at the 2-position with freshly made tributyltin deuteride in benzene at 80oC for 2 hours in the presence of a catalytic amount of AIBN generated tetra-O-acetyl-[2-2H]-deoxyglucose. Analysis by 2H NMR spectroscopy showed 2 deuterium peaks, at 1.5 and 2 ppm. Deacetylation gave the desired [2-2H]-deoxyglucose. With the same procedure tetra-O-benzoyl-[2-2H]-deoxyglucose was prepared, but not debenzoylated, so as to facilitate HPLC analysis. In a different application, the same approach was applied to tryptophan methyl ester to generate the corresponding isocyanide. This reaction is a model for a general approach to the synthesis of a-deuterium or tritium labelled carboxylic acids from amino acids. The deuterium labelling of these compounds is underway and will be completed in the near future.
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