One-pot synthesis of unsymmetrical diaryl thioethers by palladium-catalyzed coupling of two aryl bromides and a thiol surrogate.
One-pot synthesis of unsymmetrical diaryl thioethers by palladium-catalyzed coupling of two aryl bromides and a thiol surrogate.
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DOI：
10.1002/chem.200902313
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发表时间：
2010-02-22
影响因子：
4.3
通讯作者：
Hartwig, John F.
中科院分区：
文献类型：
--
作者：
Fernandez-Rodriguez, Manuel A.;Hartwig, John F.
芳香族硫醚是一种有价值的合成中间体，经常存在于生物和药物活性分子或聚合物材料中。特别是，二芳基和芳基杂芳基硫醚是许多药物的重要组成部分，在治疗炎症、癌症、人类免疫缺陷病毒（HIV）、哮喘、阿尔茨海默病和帕金森病方面具有潜在的应用。[1-6]此外，二芳基硫醚是相应的亚砜和砜的前体，它们也表现出重要的生物活性，并含有在抗真菌和抗癌药物中，以及潜在的阿尔茨海默病或HIV候选药物中。[7-11]合成这类硫醚的经典方法包括芳烃与硫的热反应，[12,13]活化氯芳烃与硫酚的碱催化反应，[14]以及有机锂或格氏试剂与氯苯基硫的缩合反应然而，这些反应通常需要苛刻的反应条件，发生的区域选择性低，并形成二硫和噻吩副产物。[12,13]为了解决这些限制，过渡金属催化的交叉偶联反应，包括钯、[16-19]镍、[20]铜、[21-23]铁、[24]和钴、[25]等配合物催化的反应，已被开发成芳香族碳硫键。虽然这些金属催化的偶联反应通常在较温和的条件下以高收率发生，但很少有芳香族硫醇在商业上可用。这种烯硫醇可以通过纽曼-克瓦特[26]和Schönberg[27]重排从苯酚中获得，但这两种过程都需要极端的热条件。此外，许多芳香硫醇不稳定氧化，这些硫醇在储存后会腐烂。因此，从H2S等价物和两种不同的芳基卤化物中生成二芳基硫醚的工艺将是对现有方法的显着改进。钯催化的硫化氢替代物，如异辛基-3-巯基丙酸盐[18,28]和三异丙基硅硫醇（TIPS-SH）或其相应的碱金属硫酸盐的反应是已知的[29-31]，但这些反应还没有发展成一个简单的序列来形成不对称的二芳基硫醚。
Aromatic thioethers are valuable synthetic intermediates frequently found in biologically and pharmaceutically active molecules or in polymeric materials. In particular, diaryl-and aryl-heteroaryl thioethers are essential components of numerous drugs with potential application in the treatment of inflammation, cancer, human immunodeficiency virus (HIV), asthma, Alzheimer’s and Parkinson’s diseases.[1–6] Furthermore, diaryl thioethers are precursors to the corresponding sulfoxides and sulfones that also exhibit important biological activities and are contained in antifungal and anti-cancer agents as well as in potential drug candidates for Alzheimer’s disease or HIV.[7–11] Classical methods for the synthesis of such thioethers encompass thermal reaction of arenes with sulfur,[12, 13] basemediated reactions of activated chloroarenes with thiophenols,[14] and condensation of organolithium or Grignard reagents with chlorophenyl sulfide.[15] However, these reactions often require harsh reaction conditions, occur with low regioselectivity, and form disulfide and thiantrene side products.[12, 13]To address these limitations, cross-coupling reactions catalyzed by transition metals, including reactions catalyzed by complexes of palladium,[16–19] nickel,[20] copper,[21–23] iron,[24] and cobalt,[25] have been developed to form aromatic carbon–sulfur bonds. Although these metal-catalyzed coupling reactions often occur in high yield under milder conditions than the uncatalyzed methods, few aromatic thiols are commercially available. Such arenethiols are accessible from phenols by Newman–Kwart [26] and Schönberg [27] rearrangements, but both processes require drastic thermal conditions. In addition, many aromatic thiols are unstable to oxidation, and these thiols can decay upon storage. Thus, a process to generate diaryl thioethers from an H2S equivalent and two different aryl halides would be a marked improvement over current methods. Palladium-catalyzed reactions of hydrogen sulfide surrogates, such as isooctyl-3-mercaptopropionate [18, 28] and triisopropylsilanethiol (TIPS-SH) or its corresponding alkali metal thiolates are known,[29–31] but these reactions have not been developed into a simple sequence to form unsymmetrical diaryl thioethers.
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影响因子：
3.5
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