It has been demonstrated that nitro groups are selectively replaced by deuterium in a variety of organic molecules (e.g., a-nitro ketones, secondary and tertiary nitro hydrocarbons) upon treatment with tributyltin deuteride. It follows that analogous use of high specific activity tributyltin tritide could lead to an extremely useful tritiation method. To demonstrate this approach, we have prepared a variety of a-deuteriated cyclic ketones via radical denitration reactions. The preliminary labelling steps involved the synthesis of a-nitroketones in one or two steps and removal of the a-nitro group with Bu3SnD in a radical reaction using AIBN as the initiator. As a test of potential labelling substrates, a tertiary cyclic ketone, an a-nitroethyl ester and several primary, secondary, and tertiary a-nitroketones were prepared as follows: a. 1-Nitroadamantane was prepared from 1-aminoadamantane in a one-step oxidation using m-CPBA in dichloroethane at 83oC for 5 hours. The product 1-nitroadamantane was characterized by NMR spectroscopy and gas chromatography. b. Ethyl a-nitromyristate: Ethyl a-bromomyristate was nitrated at the a-position with sodium nitrite in DMF in the presence of phloroglucinol dihydrate. Recrystallization from hexane furnished the product in 67% yield. c. Nitromethyladamantyl ketone: This compound was prepared using the method described in (b) from bromomethyladamantyl ketone. After several steps of purification using the chromatotron, a 34% yield of the desired product was obtained. d. 2-Nitrocholesta-3-one: 5 a-Cholesta-3-one was dissolved in dry THF and was added to a suspension of potassium-t-butoxide in THF and t-Butanol, at -30oC. A solution of isobutyl nitrate in THF was then added dropwise. The resulting mixture was acidified with HCl (2N), and was extracted with methylene chloride. The yellow residue was recrystallized from hexane:ether to give 2-nitrocholesta-3-one (60%). e. 2-Nitrocyclododecan-1-one: This product was prepared using a two step synthesis (1) 1-Acetoxy-1-cyclododecene: Cyclododecanone was added to a solution of acetic anhydride and p-toluene-sulfonic acid. The solution was heated at 175oC for 3 hours, cooled, and washed TITLE: Reductive Cleavage of Aliphatic Nitro Groups with Tributyltin Tritide (continued) with sodium bicarbonate. The residue was purified by flash chromatography using hexane as the eluting solvent. The enol acetate product was isolated in 73% yield. (2) 2-Nitro-cyclododecan-1-one: 1-Acetoxy-1-cyclododecene was nitrated using preground ammonium nitrate, followed by addition of trifluoroacetic anhydride. Recrystallization from hexane gave pure product (48%). f. [2-Nitro-2-(1-propion-1-al)]cyclododecan-1-one: 2-Nitrocyclododecan-1-one was dissolved in THF, triethylamine was added and the mixture was stirred. A mixture of acrolein in THF was added and stirred for 3 hours. Completion of the reaction gave a white product (72%). In our exploratory labelling experiments, the denitration reaction was carried out in the presence of TBTH with AIBN as the radical initiator, in refluxing toluene. Subsequent reactions with TBTD under the same reaction conditions gave deuteriated products. To further demonstrate the utility of this method in tritium labelling chemistry, one of the secondary a-nitroketones was converted to a tertiary a-nitroketone using a Michael reaction. This reaction demonstrates the role of the nitro group for activating conjugate addition of an activated double bond. The nitro group is then removed with TBTD to regioselectively introduce a deuterium atom into the new product. Deuterium labelling of the only a-nitro ethyl ester in the series was also completed to give a-deuterio ethyl myristate. All the deuteriated products were analyzed with 2H NMR, mass spectrometry and gas chromatography for the labelling specificity, deuterium content and chemical yields respectively. We will demonstrate this tritium labelling technique with some of the above precursors and use TBTT to tritiodenitrate the precursor. The chemical and radiochemical purity, and the specific radioactivity of the reaction product will be determined by gas chromatography and liquid scintillation counting and the specificity of tritium labelling will be established with 3H NMR spectroscopy. The preliminary deuteriation reactions of this project were completed during this r e se arch period.
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