A Unified Approach to Couple Aromatic Heteronucleophiles to Azines and Pharmaceuticals.
A Unified Approach to Couple Aromatic Heteronucleophiles to Azines and Pharmaceuticals.
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DOI：
10.1002/anie.201807322
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发表时间：
2018-09-17
期刊：
影响因子：
--
通讯作者：
McNally A
中科院分区：
文献类型：
--
作者：
Anderson RG;Jett BM;McNally A
将芳香族杂核剂与芳烃偶联是组装类药物分子的一种常见方法。许多方法是通过亲核剂截取有机金属中间体，通过钯、铜和镍催化，促进碳-杂原子键的形成和各种方案。我们提出了一种替代的、统一的策略，在该策略中，膦盐可以复制有机金属中间体的行为。在一系列狭窄的反应条件下，各种芳香族杂核亲核试剂可以偶联到吡啶和二氮杂环上，这在金属催化的偶联反应中经常是有问题的，例如在具有多个极性官能团的复杂结构中(假)卤化物前体是不可用的。芳香族杂核剂，如苯酚、硫酚、苯胺、咪唑和吡唑类化合物，经常与吡啶和二氮杂环偶联，形成类药物分子。金属催化剂最常用于促进这种转化，但各种各样的反应方案和复杂的催化循环会限制它们在复杂杂环中的使用。我们提出了一种替代的方法，其中七种不同类别的亲核试剂通过亲核加成-P-配体偶联机制与氮杂膦盐偶联。这种方法的优点是反应条件范围窄，适用于类药物片段和复杂的生物活性分子。
Coupling aromatic heteronucleophiles to arenes is a common way to assemble drug-like molecules. Many methods operate via nucleophiles intercepting organometallic intermediates, via Pd-, Cu- and Ni-catalysis, that facilitate carbon-heteroatom bond-formation and a variety of protocols. We present an alternative, unified strategy where phosphonium salts can replicate the behavior of organometallic intermediates. Under a narrow set of reaction conditions, a variety of aromatic heteronucleophile classes can be coupled to pyridines and diazines that are often problematic in metal-catalyzed couplings, such as where (pseudo)halide precursors are unavailable of in complex structures with multiple polar functional groups. Aromatic heteronucleophiles, such as phenols, thiophenols, anilines, imidazoles and pyrazoles, are frequently coupled to pyridine and diazine heterocycles to make drug-like molecules. Metal catalysts are most commonly used to facilitate this transformation, but the wide variety of reaction protocols and complex catalytic cycles can limit their use for complex heterocycles. We present an alternative approach where seven distinct classes of nucleophiles are coupled to azine phosphonium salts via a nucleophile addition-P-ligand coupling mechanism. A narrow range of reaction conditions and applicability to drug-like fragments as well as complex bioactive molecules are advantages of this approach.
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