REDUCTIVE CLEAVAGE OF ALIPHATIC NITRO GROUPS W/ TRIBUTYLTIN TRITIDE: TRITIUM NMR

已证明硝基是选择性的 在各种有机分子(例如，_-硝基)中被重氢取代 酮、二、叔位硝基碳氢化合物) 用三丁基四氢化锡。它遵循了High的类似用法 比活度三丁基锡三肽可能导致极端 实用的氚测定方法。为了演示这种方法，我们有 通过自由基合成了多种氢代环酮类化合物 脱氮反应。初步的标签步骤包括 一步或两步合成_-硝基酮及其脱除 _-硝基与Bu3SnD(TBTD)的自由基反应 以偶氮二异丁腈(AIBN)为引发剂。作为对 潜在的标记底物，叔环酮，和 _-硝乙酯和几种伯基、仲基和叔基 _-硝基酮的制备方法如下：a.1-硝基金刚烷 以1-氨基金刚烷为原料，一步氧化制得 3-氯过氧苯甲酸(m-CPBA)在83oC的二氯乙烷中5 几个小时。产物1-硝基金刚烷经核磁共振表征 光谱分析和气相色谱。B.硝基肉豆蔻酸乙酯： 溴氰酸乙酯与钠在_-位硝化 间苯三酚存在下二甲基甲酰胺(DMF)中的亚硝酸盐 二水合物。正己烷的重结晶提供了67%的产品 投降。C.硝甲基金刚烷基酮：该化合物是由 使用(B)中所述的方法从溴甲基金刚烷基酮中合成。 在使用色谱仪进行几个步骤的纯化后，34% 得到了所需产品的产率。D.2-硝基-3-酮： 5-胆烷-3-酮溶于干四氢呋喃(THF)， 加入叔丁醇钾在四氢呋喃和叔丁醇中的悬浮液中， -30摄氏度。然后滴加硝酸异丁酯在四氢呋喃中的溶液。 得到的混合物用HCl(2N)酸化，然后被提取 用二氯甲烷。黄色残留物是从 正己烷：乙醚生成2-硝基-3-酮(60%)。E. 2-硝基十二烷-1-酮：本产品经两步反应制得 合成(1)1-乙酰氧基-1-环十二烯：环十二酮加成 乙酸酐和对甲苯磺酸的溶液。这个 溶液在175摄氏度下加热3小时，冷却，并用 碳酸氢钠。残留物用闪蒸层析法提纯 以正己烷为洗脱溶剂。乙酸烯醇酯产品为 分离得率为73%。(2)2-硝基-环十二烷-1-酮： 1-乙酰氧基-1-环十二烯用预硝化铵硝化 硝酸盐，然后加入三氟乙酸酐。 正己烷重结晶得到纯产物(48%)。F. [2-Nitro-2-(1-propion-1-al)]cyclododecan-1-one： 2-硝基十二烷-1-酮溶于四氢呋喃，三乙胺 加入，混合物被搅拌。丙烯醛在四氢呋喃中的混合物是 加入，搅拌3小时。反应的完成给出了一个 白色产品(72%)。在我们的探索性标签实验中， 在四叔丁基四氢呋喃与AIBN的存在下进行脱氮反应 作为自由基引发剂，在甲苯中回流。后续反应 与TBTD在相同的反应条件下给出了氢化反应 产品。为了进一步演示此方法在 氚标记化学，其中一种仲硝酮是 通过迈克尔反应转化为叔硝酮。这 反应证明了硝基的活化作用 活化的双键的共轭加成。硝基是 然后用tbtd除去以区域选择性地引入一个氢原子。 投入到新产品中。唯一硝基乙基化合物的氚标记 该系列中的酯类也已完成，以给出__重水乙基 肉豆蔻。用~2H核磁共振对所有的氢化产物进行了分析， 用于标记物的质谱分析和气相色谱 专属性、氚含量和化学产额。我们 已经将这种方法应用于标签的氚检测 上述(C)和(E)中合成的前体。作为第一个例子， 叔丁基叔丁基四甲基金刚烷酮的自由基三碘代硝化 (25%氚)提供67%的产品，比活度为6.7 Ci/MMole。对产物进行了LSC、RADIO-GC、1H和 用~3H核磁共振波谱确证其含量、纯度和特异性 氚标记。对于第二个例子，三碘代硝化 2-硝基环十二烷-1-酮得到所需产物和 一些无法辨认的副产品。混合物的GC分析， 包括产品峰的收集和定量，显示出 比活度为5.6Ci/毫摩尔，化学产率为12%。这些 两个氚的例子将包括在一个详细的手稿中 展示了脱氮反应作为一种选择性的 贴标签的方法。

It has been demonstrated that nitro groups are selectively replaced by deuterium in a variety of organic molecules (e.g., _-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 _-deuteriated cyclic ketones via radical denitration reactions. The preliminary labelling steps involved the synthesis of _-nitroketones in one or two steps and removal of the _-nitro group with Bu3SnD (TBTD) in a radical reaction using azobisisobutyronitrile (AIBN) as the initiator. As a test of potential labelling substrates, a tertiary cyclic ketone, an _-nitroethyl ester and several primary, secondary, and tertiary _-nitroketones were prepared as follows: a. 1-Nitroadamantane was prepared from 1-aminoadamantane in a one-step oxidation using 3-chloroperoxybenzoic acid (m-CPBA) in dichloroethane at 83oC for 5 hours. The product 1-nitroadamantane was characterized by NMR spectroscopy and gas chromatography. b. Ethyl _-nitromyristate: Ethyl _-bromomyristate was nitrated at the _-position with sodium nitrite in dimethylformamide (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 _-Cholesta-3-one was dissolved in dry tetrahydrofuran (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 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 __nitroketones was converted to a tertiary __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 __nitro ethyl ester in the series was also completed to give __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 have applied this approach to the tritiation of the labelling precursors synthesized in (c) and (e) above. As a first example, radical tritiodenitration of _-nitromethyladamantanyl ketone with TBTT (25% tritium) gave 67% of a product with specific activity 6.7 Ci/mmole. The product was analyzed by LSC, radio-GC and both 1H and 3H NMR spectroscopy to confirm the amount, purity and specificity of tritium labelling. For the second example, the tritiodenitration of 2-nitrocyclododecan-1-one gave a mixture of the desired product and some unidentifiable side products. GC analysis of the mixture, including collection and quantitation of the product peak, showed a specific activity of 5.6 Ci/mmole and a chemical yield of 12%. These two tritiation examples will be included in a detailed manuscript demonstrating the use of denitration reactions as a selective labelling approach.