Nambu Hisanori, Seto Yuki, Onuki Yuta, Yamazaki Koga, Tomohara Keisuke, Yakura Takayuki
Faculty of Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, 930-0194, Japan.
Laboratory of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, Kyoto, 607-8412, Japan.
Chem Asian J. 2025 Aug;20(16):e00262. doi: 10.1002/asia.202500262. Epub 2025 May 14.
A novel approach for the construction of the benzo[b]thiophene skeleton has been developed. Regioselective ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes using sodium hydrosulfide as a sulfur-transfer reagent proceeded smoothly and subsequent addition of an acid afforded the corresponding tetrahydrobenzo[b]thiophen-4-one derivatives in good to excellent yields. Cycloheptane-1,3-dione-2-spirocyclopropanes could be also applied to the present protocol. In contrast, the reaction of monocyclic 1,1-diacetyl-2-phenylcyclopropane with sodium hydrosulfide and subsequent addition of an acid gave decomposition products instead of the desired product. This result suggests that the spiro structure is crucial for successful ring-opening cyclization. One of the products obtained from cyclohexane-1,3-dione-2-spirocyclopropanes could be converted into the 2-substituted 4-hydroxybenzo[b]thiophene derivative while avoiding oxidation of the sulfide to sulfoxide or sulfone. This protocol provides an alternative synthetic method to access benzo[b]thiophenes without using multisubstituted benzenes as starting materials, which are often difficult to prepare. To our knowledge, this is the first report of the synthesis of benzo[b]thiophenes from cyclopropanes.
一种构建苯并[b]噻吩骨架的新方法已经开发出来。使用硫化氢钠作为硫转移试剂，环己烷-1,3-二酮-2-螺环丙烷的区域选择性开环环化反应顺利进行，随后加入酸，以良好至优异的产率得到相应的四氢苯并[b]噻吩-4-酮衍生物。环庚烷-1,3-二酮-2-螺环丙烷也可应用于本方法。相比之下，单环1,1-二乙酰基-2-苯基环丙烷与硫化氢钠反应，随后加入酸，得到的是分解产物而非所需产物。这一结果表明螺环结构对于成功的开环环化至关重要。从环己烷-1,3-二酮-2-螺环丙烷得到的产物之一可以转化为2-取代的4-羟基苯并[b]噻吩衍生物，同时避免硫化物氧化为亚砜或砜。该方法提供了一种无需使用多取代苯作为起始原料来合成苯并[b]噻吩的替代合成方法，多取代苯通常难以制备。据我们所知，这是首次报道从环丙烷合成苯并[b]噻吩。
