The chemistry of vanillin (1) and isovanillin (2) has been examined and reviewed extensively.1–3 A current project in our laboratory required the conversion of 5-iodoisovanillin ethers 6a–d to substituted 2,4-diaminopyrimidines followed by Heck coupling with an unsaturated ketone to generate agents displaying inhibitory activity against Bacillus anthracis, a potential bioterror threat.4 The chemistry to prepare 5-iodovanillin ethers 6a–d with variation at C-4 is straightforward5,6 starting from commercial 5-iodovanillin (3).7,8 Procedures to alter the C-3 alkoxy group, however, require demethylation of 3 to give catechol 4 followed by sequential methylation at the C-4 hydroxy group followed by O-alkylation at C-3. The synthesis of 5-iodoisovanillin ethers 6a–d, thus, requires regiocontrol in the initial methylation of 4. Although preferential alkylation of the C-4 hydroxy group of 4 would be expected due to its greater activation by the C-1 aldehyde, controlling this process to give clean monoalkylation is necessary. This has been achieved, and we now report a concise and selective method to generate 5-iodoisovanillin ethers. Isovanillin, iodinated at C-5, has been previously reported, but the synthetic routes were lengthy9 or the procedures were unclear.10 In the first synthesis,9 the iodo group was introduced by a diazotization-replacement sequence as part of a six-step preparation from isovanillin. In the second procedure,10 the methyl ether was cleaved with aluminum chloride-pyridine and selectively alkylated at the C-4 hydroxyl group using methyl iodide and sodium bicarbonate in N,N-dimethylformamide-acetone. This approach parallels our procedure, but lacks detail about the isolation of the product from the precipitated material following decomposition of the aluminum chloride. Additionally, we had trouble controlling the subsequent alkylation using this method. Our synthesis of 5-iodoisovanillin ethers 6a–d is outlined in Scheme 1. Demethylation of 5-iodovanillin (3) with aluminum chloride-pyridine led to 3,4-dihydroxy-5-iodobenzaldehyde (4) in 80% yield.10,11 The use of this reagent to cleave the ether was selected over anhydrous HBr in acetic acid12 and boron tribromide12 due to the simpler procedure, reduced hazard and lower cost. Following cleavage of the C-3 ether, regio-selective alkylation of the C-4 hydroxy group of 4 proceeded cleanly by treatment with 1.1 equivalent of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in N,N-dimethylformamide (DMF) followed by addition of several portions of methyl iodide. This procedure afforded 5-iodoisovanillin 5 in 79% yield after flash chromatography. A similar alkylation using sodium bicarbonate,10 lithium carbonate13 or sodium carbonate in DMF yielded the C-4-monomethylated product in ≤30%, along with recovered starting material and the dialkylated product. The current procedure to generate 4 and 5 is superior to the previously reported syntheses in terms of yield, regiocontrol and time required. The target compounds required a final O-alkylation of the C-3 hydroxy group of 5 to give previously unknown derivatives 6a–d. Again, the use of DBU/DMF as the catalyst/solvent system for this transformation gave complete conversion in slightly more than one hour at room temperature. Purification by flash chromatography produced 6a–d in yields ranging from 78–92%. Finally, our attempts to improve the yield of 6c by carrying out the reaction in other solvents (tetrahydrofuran or dichloromethane) and with other bases (potassium carbonate or tri-ethylamine) resulted in lower yields of the desired product. Related systems 7 and 8 were synthesized similarly. Treatment of 4 with 3.5 equivalents of DBU and 3.0 equivalents of ethyl iodide produced 7 as a pale yellow solid in 80% yield. Likewise, 4 reacted with 3.5 equivalents of DBU and 1.1 equivalent of diiodomethane gave 7-iodo-1,3-benzodioxole-5-carbaldehyde (8) in 78% yield.14 Spectral and elemental analyses confirmed the structures of the final targets 6–8. Interestingly, 8 retained traces of methanol, following recrystallization from this solvent, even after extensive drying under high vacuum. Scheme 1 In summary, we have successfully developed a straightforward approach by which derivatives of 5-iodovanillin and 5-iodoisovanillin can be prepared. The use of aluminum chloride in pyridine proved most convenient and cost effective for the cleavage of the methyl ether in 5-iodovanillin (3) to generate 3,4-dihydroxy-5-iodobenzaldehyde (4). Regiospecific O-alkylation of 4 at the C-4 hydroxy group with methyl iodide in DBU/DMF then provided 5, which could be further alkylated at the C-5 hydroxy group using the same conditions to afford the series 6a–d. The basic procedure was further extended to the preparation of 7 and 8.

中文翻译：

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香兰素和异香兰素的碘化衍生物的研究

香兰素 (1) 和异香兰素 (2) 的化学性质已被广泛检查和审查。 1-3 我们实验室当前的一个项目需要将 5-碘异香兰素醚 6a-d 转化为取代的 2,4-二氨基嘧啶，然后进行 Heck 偶联用不饱和酮生成对炭疽芽孢杆菌具有抑制活性的试剂，这是一种潜在的生物恐怖威胁。4 制备 5-碘香兰素醚 6a-d 的化学反应在 C-4 处发生变化很简单 5,6 从商业 5-碘香兰素 (3) 开始.7,8 然而，改变 C-3 烷氧基的程序需要将 3 去甲基化以得到邻苯二酚 4，然后在 C-4 羟基上连续甲基化，然后在 C-3 上进行 O-烷基化。因此，5-碘异香草醛醚 6a-d 的合成需要在 4 的初始甲基化中进行区域控制。尽管 4 的 C-4 羟基由于其被 C-1 醛更大的活化而预期会优先烷基化，但控制该过程以提供干净的单烷基化是必要的。这已经实现，我们现在报告了一种生成 5-碘异香草醛醚的简洁且选择性的方法。在 C-5 处碘化的异香草醛之前已有报道，但合成路线冗长 9 或程序不清楚。 10 在第一次合成中，9 碘基团是通过重氮化-置换序列引入的，作为六步的一部分从异香草醛制备。在第二个程序中，10 甲基醚用氯化铝-吡啶裂解，并在 N,N-二甲基甲酰胺-丙酮中使用碘甲烷和碳酸氢钠在 C-4 羟基上选择性地烷基化。这种方法与我们的程序相似，但缺乏关于在氯化铝分解后从沉淀材料中分离产物的详细信息。此外，我们无法使用这种方法控制随后的烷基化。我们合成的 5-碘异香草醛醚 6a-d 在方案 1 中进行了概述。 5-碘香兰素 (3) 与氯化铝-吡啶的去甲基化导致 3,4-二羟基-5-碘苯甲醛 (4) 的产率 80%。 10, 11 选择使用该试剂裂解乙醚，而不是无水 HBr 的乙酸溶液 12 和三溴化硼 12，原因是程序更简单、危害更小且成本更低。在 C-3 醚裂解后，4 的 C-4 羟基的区域选择性烷基化通过用 1.1 当量的 1,8-二氮杂双环 [5.4.0] 十一碳-7-烯 (DBU) 在 N 中处理而干净地进行, N-二甲基甲酰胺 (DMF)，然后加入几份甲基碘。该程序在快速色谱后以79%的产率提供5-碘​​异香草醛5。使用碳酸氢钠、10 碳酸锂 13 或碳酸钠在 DMF 中进行类似的烷基化产生≤30% 的 C-4-单甲基化产物，以及回收的起始材料和二烷基化产物。当前生成 4 和 5 的程序在产量、区域控制和所需时间方面优于先前报道的合成。目标化合物需要对 5 的 C-3 羟基进行最终的 O-烷基化，以得到以前未知的衍生物 6a-d。同样，使用 DBU/DMF 作为该转化的催化剂/溶剂系统，在室温下在一小时多一点的时间内完全转化。通过快速色谱法纯化产生 6a-d，产率范围为 78-92%。最后，我们通过在其他溶剂（四氢呋喃或二氯甲烷）和其他碱（碳酸钾或三乙胺）中进行反应来提高 6c 收率的尝试导致所需产物的收率较低。类似地合成相关系统7和8。用3.5当量的DBU和3.0当量的碘乙烷处理4以80%的收率产生浅黄色固体形式的7。同样，4 与 3.5 当量 DBU 和 1.1 当量二碘甲烷反应得到 7-iodo-1,3-benzodioxole-5-carbaldehyde (8)，产率为 78%。14 光谱和元素分析证实了最终目标的结构 6– 8. 有趣的是，从该溶剂中重结晶后，有 8 种保留了痕量甲醇，即使在高真空下大量干燥后。方案 1 总而言之，我们已经成功地开发了一种直接的方法，通过该方法可以制备 5-碘香兰素和 5-碘异香兰素的衍生物。事实证明，在吡啶中使用氯化铝对于裂解 5-碘香兰素 (3) 中的甲基醚以生成 3,4-二羟基-5-碘苯甲醛 (4) 来说是最方便且成本有效的。然后在 DBU/DMF 中用碘甲烷对 C-4 羟基上的 4 进行区域特异性 O-烷基化，然后提供 5，可以使用相同的条件在 C-5 羟基上进一步烷基化，得到 6a-d 系列。基本程序进一步扩展到7和8的制备。事实证明，在吡啶中使用氯化铝对于裂解 5-碘香兰素 (3) 中的甲基醚以生成 3,4-二羟基-5-碘苯甲醛 (4) 来说是最方便且成本有效的。然后在 DBU/DMF 中用碘甲烷对 C-4 羟基上的 4 进行区域特异性 O-烷基化，然后提供 5，可以使用相同的条件在 C-5 羟基上进一步烷基化，得到 6a-d 系列。基本程序进一步扩展到7和8的制备。事实证明，在吡啶中使用氯化铝对于裂解 5-碘香兰素 (3) 中的甲基醚以生成 3,4-二羟基-5-碘苯甲醛 (4) 来说是最方便且成本有效的。然后在 DBU/DMF 中用碘甲烷对 C-4 羟基上的 4 进行区域特异性 O-烷基化，然后提供 5，可以使用相同的条件在 C-5 羟基上进一步烷基化，得到 6a-d 系列。基本程序进一步扩展到7和8的制备。可以使用相同的条件在 C-5 羟基上进一步烷基化，得到 6a-d 系列。基本程序进一步扩展到7和8的制备。可以使用相同的条件在 C-5 羟基上进一步烷基化，得到 6a-d 系列。基本程序进一步扩展到7和8的制备。