Revisiting benzenesulfonyl linker for the deoxygenation and multifunctionalization of phenols
Revisiting benzenesulfonyl linker for the deoxygenation and multifunctionalization of phenols
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DOI：
10.1021/cc0600066
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发表时间：
2006-05-01
影响因子：
--
通讯作者：
Kondo, Y
中科院分区：
文献类型：
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作者：
Tsukamoto, H;Suzuki, R;Kondo, Y
芳烃和杂芳烃是药物和材料科学领域中的重要类别。发现具有有趣的生物活性和功能的芳烃需要大量的时间和劳动。基于组合化学的固相合成技术使许多芳香族化合物的快速制备成为可能，并推动了芳香族化合物的发现进程。固相合成中的一个关键组成部分是用于将分子连接到固体支持物上的连接体。无痕连接体代表了固相有机合成的一个令人兴奋的方面，因为希望使分子缺乏任何外来的功能。[1]虽然已经开发了几种用于连接芳烃的无痕连接剂，但它们有自己的局限性。第14族金属基连接体2和三氮烯型连接体3需要在连接到树脂之前预活化初始结构单元，即芳基卤化物的金属化和由母体苯胺形成重氮盐。另一方面，酰肼4和硼酸酯5连接体仅限于具有相对较少商业成员的起始材料类别。苯磺酸酯连接体6 -8摆脱了这些限制，其中市售聚苯乙烯磺酰氯（PS-SO2 Cl）9和市售酚类的直接和容易的偶联是可能的，而无需预先修饰。但由于苯磺酰基的活化能力较差，只有缺电子酚类化合物可以在Pd（OAc）2/1，3-双（二苯基膦基）丙烷（dppp）催化下进行脱氧。为了改善差的反应性，已经开发了一些缺电子的“三氟甲磺酸酯样”连接体10，但是现在需要它们的制备。苯磺酰基连接体的商业可用性和化学稳定性足以吸引我们重新研究适用于富电子苯酚磺酸盐的Pd催化还原裂解条件。Hartwig's 11和Buchwald's 12研究组在Pd催化的芳基苯磺酸盐的碳-碳和碳-氮键形成方面的最新进展表明，与Pd（0）配位的膦配体在克服反应活性差方面起着重要作用。我们现在希望描述配体对Pd催化的还原裂解的对甲苯磺酸盐和树脂结合的苯磺酸盐的富电子苯酚的影响。我们还将该接头的应用扩展到一种策略，即在裂解步骤中可以将额外的官能团附加到芳环上。反应在DMF中进行，在100 ℃加热，用过量的甲酸和三乙胺作为还原剂，在催化量的Pd（OAc）2和一系列膦配体存在下进行. 1中的给电子乙酰胺基团阻碍了与双（二苯基膦）如dppp、dppb和dppf连接的钯的裂解（条目1-3）。使用更多的σ-供体双（二烷基膦）得到少量的还原产物2a（条目4、5）。这些结果表明1氧化加成到Pd（0）络合物中应该是一个速率决定步骤。虽然Buchwald开发的空间位阻单膦2-（二环己基膦基）-2′，4′，6′-三异丙基-1，1′-联苯（X-PHOS）15的效果较差12，但Hartwig 11使用的空间位阻双膦PPF-t-Bu 15被证明对裂解最有效（条目6，7）。进一步优化了反应条件，发现以t-BuOH为溶剂可使1，2-二氯乙烷完全转化。
Arenes and heteroarenes are important classes in the field of pharmaceutical and material sciences. Discovery of the arenes possessing interesting biological activities and functions should require enormous time and labor. Solid-phase synthesis based on combinatorial chemistry has enabled rapid preparation of a lot of aromatic compounds and promoted the discovery process. A key component in solid-phase synthesis is the linker that is used to attach the molecules to the solid support. Traceless linkers represent an exciting aspect of solid-phase organic synthesis due to the desire to make molecules lacking any extraneous functionality. 1 Although several traceless linkers for attachment of the arenes have been developed, they have their own limitations. Group 14 metal-based linkers2 and triazene-type linkers3 require preactivation of the initial building block prior to attachment to the resin, ie, metalation of aryl halides and formation of diazonium salts from the parent anilines, respectively. On the other hand, hydrazide4 and boronate5 linkers are restricted to classes of starting materials with relatively few commercial members. Benzenesulfonate linker6-8 gets rid of these limitations where the direct and facile coupling of commercially available polystyrene sulfonyl chloride (PS-SO2Cl) 9 and also commercially available phenols was possible without prior modification. However, only electron-deficient phenols could be deoxygenated under Pd (OAc) 2/1, 3-bis (diphenylphosphino) propane (dppp) catalysis due to the poor activating ability of the benzenesulfonyl group. To improve the poor reactivity, some electrondeficient ‘triflate-like’linkers10 have been developed, but their preparation is now required. The commercially availability and chemical stability of the benzenesulfonyl linker were enough attractive to drive us to reinvestigate the Pd-catalyzed reductive cleavage conditions applicable to the sulfonates of electron-rich phenols. Recent advance in Pd-catalyzed carbon-carbon and carbon-nitrogen bond formation using aryl benzenesulfonates reported by Hartwig’s11 and Buchwald’s12 groups illustrates that phosphine ligands coordinated to the Pd (0) plays an important role to overcome the poor reactivity. We now wish to describe the ligand effect on the Pd-catalyzed reductive cleavage of p-toluenesulfonates and resin-bound benzenesulfonates of electron-rich phenols. We also expand application of this linker to a strategy whereby additional functionality can be appended to the aryl ring during the cleavage step.This effort began by ligand screening for the Pd-catalyzed reductive cleavage of acetamide-substituted p-toluenesulfonate 113 (Table 1). The reaction was carried out in DMF on heating at 100 C with an excess of formic acid and triethylamine as reducing agents in the presence of a catalytic amount of Pd (OAc) 2 and a series of phosphine ligands. The electron-donating acetamide group in 1 hindered the cleavage with the palladium ligated with bis (diphenylphosphine) such as dppp, dppb, and dppf (entries 1-3). 14 The use of more σ-donating bis (dialkylphosphine) afforded a small amount of the reduction product 2a (entries 4, 5). These results suggest oxidative addition of 1 to the Pd (0) complex should be a rate-determining step. While 2-(dicyclohexylphosphino)-2′, 4′, 6′-tri-i-propyl-1, 1′-biphenyl (X-PHOS) 15 as a sterically hindered monophosphine developed by Buchwald12 was less effective, PPF-t-Bu15 as a sterically hindered bis (phosphine) employed by Hartwig11 proved to be the most effective for the cleavage (entries 6, 7). Further optimization of reaction conditions revealed that t-BuOH as solvent completely converted 1 …