In connection with our program directed toward the development of structure-activity relationships of cannabimimetic 1-alkyl-3-(1-naphthoyl)indoles1,2 we needed synthetically useful quantities of 8-chloro-1-naphthoic acid (1). The synthesis of acid 1 from 1,8-naphthalic anhydride (2) via anhydro-8-hydroxymercuri-1-naphthoic acid (3) and 8-chloromercuri-1-naphthoic acid (4) by treatment with the elemental halogen was described originally by Whitmore during the course of his studies on the mercuration of aromatic compounds is shown in Scheme 1.3,4 A modification of the Whitmore procedure was employed by Rule and Barnett to obtain modest yields of acid 1 and 8-bromo-1-naphthoic acid (5).5 Although Rule and Barnett mention that 8-chloromercuri-1-naphthoic acid was prepared as described by Leuck et al.3 there is no mention of chloromercuri acid 4 in the paper which was cited. However the preparation of a mixture of acid 4 and its 5-isomer was described by Whitmore and Fox.4 Although acid 1 has been the subject of several physical organic studies, either no reference is given to the method of synthesis, or reference was given to the Whitmore-Rule procedure.6–9 Shechter’s group modified the classical Whitmore procedure and employed it for the preparation of 8-bromo acid (5) and extended it to the preparation of 8-iodo-1-naphthoic acid (6).10 These workers employed anhydro-8-hydroxymercuri-1-naphthoic acid (3) as an intermediate, however treatment of 3 with chlorine gave 5,8-dichloro-1-naphthoic acid (7) as the only isolable product. Scheme 1 a) 0.58 M NaOH, H2O, reflux: b) Hg(OAc)2, from HgO, HOAc, reflux 48 h: c) NaOH, NaCl followed by HCl; d) Cl2, HOAc. We were able to repeat the preparation of anhydro acid 3 and its reaction with bromine and iodine to provide bromo and iodo acids 5 and 6 in unoptimized yields of 84% and 52% respectively.11 Initially, in order to avoid the use of elemental chlorine and hopefully to suppress the formation of 5,8-dichloro-1-naphthoic acid, numerous attempts were made under a variety of conditions to prepare acid 1 by reaction of anhydro acid 3 with N-chlorosuccinimide or 1,3-dichloro-5,5-dimethylhydantoin as a chlorine source. In one experiment a 36% yield of crude acid 1 was obtained; however, this compound could not be obtained even under apparently identical conditions. In another run, the crude reaction products were converted to mixtures of methyl esters, which were analyzed by GC/MS. The principal constituents of this mixture were methyl 8-chloro-1-naphthoate (41%) and a dichloro ester, presumably methyl 5,8-dichloro-1-naphthoate (53%). A methyl trichloro-1-naphthoate (7%) was found in low yield but was not otherwise characterized. 8-Chloromercuri-1-naphthoic acid (4) was prepared from 1,8-naphthalic acid as described by Whitmore and Fox.4 Reaction of 4 with chlorine in acetic acid at room temperature gave a mixture of carboxylic acids that was converted to the corresponding methyl esters using CH3I and K2CO3 in dried acetone. Analysis of this mixture by GC/MS indicated that the original reaction mixture contained 8-chloro-1-naphthoic acid (1, 17%), 5,8-dichloro-1-naphthoic acid (7, 28%) and 1-naphthoic acid (28%). In another experiment methyl 8-chloro-1-naphthoate was isolated by chromatography and hydrolyzed (KOH/H2O) to provide 8-chloro-1-naphthoic acid 1 in poor (35%) yield. The presence of 5,8-dichloro-1-naphthoic acid in the mixture of chlorination products was confirmed by preparation of an authentic sample via chlorination of 8-chloro-1-naphthoic acid.4 Not only was the chromatographic purification of the methyl ester tedious, but repeated repetition of this procedure did not reliably produce 8-chloro-1-naphthoic acid; it was concluded that since electrophilic chlorination of 8-chloro-1-naphthoic acid affords 5,8-dichloro-1-naphthoic acid occurs under very mild acid catalysis,4 the formation of the 5,8-dichloro acid in the reaction of 4 with chlorine was the result of further chlorination of the desired product. Accordingly, the reaction was carried out in a 1:1 mixture of acetic acid and dichloromethane at ice bath temperature, and in several experiments this procedure provided acid 1; however, the results were variable and frequently mixtures of products, including 1-naphthoic acid, were obtained. In Rule and Barnett’s modification of Whitmore’s procedure, it is explicitly stated that dried 8-chloromercuri-1-naphthoic acid (4) be employed.5 It was ultimately found that it is essential that this key intermediate is dried in a vacuum oven at a temperature not to exceed 50°C. The 8-chloromercuri acid (4) is thermally unstable and decomposes at temperatures greater than 50°C, as indicated by changes in the 1H NMR spectrum. This procedure provides a reliable method for the preparation of 8-chloro-1-naphthoic acid (1). The 1H and 13C NMR spectra of this product are in agreement with the assigned structure, which was confirmed by X-ray crystallography.

中文翻译：

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8-Chloro- 和 5,8-Dichloro-1-naphthoic Acids

结合我们旨在开发大麻模拟物 1-烷基-3-(1-萘甲酰基) 吲哚 1,2 的构效关系的计划，我们需要合成有用数量的 8-氯-1-萘甲酸 (1)。最初描述了通过用元素卤素处理从 1,8-萘二甲酸酐 (2) 经 anhydro-8-hydroxymercuri-1-naphthoic 酸 (3) 和 8-chloromercuri-1-naphthoic 酸 (4) 合成酸 1由 Whitmore 在他研究芳香族化合物的汞化的过程中显示在方案 1.3,4 中。 Rule 和 Barnett 使用 Whitmore 程序的修改来获得适度的酸 1 和 8-bromo-1-naphthoic 酸（ 5).5 虽然 Rule 和 Barnett 提到 8-chloromercuri-1-naphthoic 酸是按照 Leuck 等人的描述制备的。3 引用的论文中没有提到氯汞酸 4。然而，Whitmore 和 Fox 描述了酸 4 及其 5-异构体混合物的制备。 4 虽然酸 1 已成为多项物理有机研究的主题，但要么没有给出合成方法的参考，要么给出了参考6-9 Shechter 小组修改了经典的 Whitmore 程序，并将其用于制备 8-溴酸 (5)，并将其扩展到制备 8-iodo-1-naphthoic 酸 (6)。 10 这些工作人员使用脱水-8-羟基汞-1-萘甲酸 (3) 作为中间体，但是用氯处理 3 得到 5,8-二氯-1-萘甲酸 (7) 作为唯一可分离的产物。方案 1 a) 0.58 M NaOH，H2O，回流：b) Hg(OAc)2，来自 HgO，HOAc，回流 48 小时：c) NaOH，NaCl，然后是 HCl；d) Cl2、HOAc。我们能够重复制备无水酸 3 及其与溴和碘的反应，分别以未优化的 84% 和 52% 的收率提供溴酸和碘酸 5 和 6。 11 最初是为了避免使用元素氯为了抑制 5,8-二氯-1-萘甲酸的形成，人们在各种条件下进行了多次尝试，通过脱水酸 3 与 N-氯代琥珀酰亚胺或 1,3-二氯-5 的反应来制备酸 1， 5-二甲基乙内酰脲作为氯源。在一项实验中，粗酸 1 的产率为 36%；然而，即使在明显相同的条件下也无法获得这种化合物。在另一次运行中，粗反应产物被转化为甲酯的混合物，通过 GC/MS 进行分析。该混合物的主要成分是 8-氯-1-萘甲酸甲酯（41%）和二氯酯，大概是 5,8-二氯-1-萘甲酸甲酯（53%）。发现三氯 1-萘甲酸甲酯 (7%) 的收率很低，但没有其他特征。8-Chloromercuri-1-naphthoic acid (4) 由 1,8-naphthalic acid 制备，如 Whitmore 和 Fox 所述。4 4 与氯在室温下在乙酸中反应得到羧酸混合物，该混合物转化为在干燥的丙酮中使用 CH3I 和 K2CO3 生成相应的甲酯。通过 GC/MS 对该混合物的分析表明，原始反应混合物含有 8-氯-1-萘甲酸（1, 17%）、5,8-二氯-1-萘甲酸（7, 28%）和 1-萘甲酸酸 (28%)。在另一个实验中，8-氯-1-萘甲酸甲酯通过色谱分离并水解（KOH/H2O）以提供8-氯-1-萘甲酸1，产率很低（35%）。5,8-二氯-1-萘甲酸在氯化产物混合物中的存在通过8-氯-1-萘甲酸的氯化制备真实样品得到证实。4 不仅是甲酯的色谱纯化繁琐但反复重复此过程并不能可靠地产生 8-chloro-1-naphthoic 酸；得出的结论是，由于 8-氯-1-萘甲酸的亲电氯化得到 5,8-二氯-1-萘甲酸是在非常温和的酸催化下发生的，4 在 4 的反应中形成 5,8-二氯酸与氯的反应是进一步氯化所需产物的结果。因此，该反应在冰浴温度下在乙酸和二氯甲烷的 1:1 混合物中进行，并且在几个实验中该程序提供了酸 1；然而，结果是可变的，并且经常获得产品的混合物，包括 1-萘甲酸。在 Rule 和 Barnett 对 Whitmore 程序的修改中，明确指出使用干燥的 8-氯汞-1-萘甲酸 (4)。5 最终发现必须在真空烘箱中以温度不超过 50°C。8-氯汞酸 (4) 是热不稳定的，在高于 50°C 的温度下会分解，如 1H NMR 谱的变化所示。此过程为 8-氯-1-萘甲酸 (1) 的制备提供了可靠的方法。