Kim Ji Hye, Constantin Timothée, Simonetti Marco, Llaveria Josep, Sheikh Nadeem S, Leonori Daniele
Department of Chemistry, University of Manchester, Manchester, UK.
Discovery Chemistry, Janssen Research and Development, Toledo, Spain.
Nature. 2021 Jul;595(7869):677-683. doi: 10.1038/s41586-021-03637-6. Epub 2021 May 20.
Boron functional groups are often introduced in place of aromatic carbon-hydrogen bonds to expedite small-molecule diversification through coupling of molecular fragments. Current approaches based on transition-metal-catalysed activation of carbon-hydrogen bonds are effective for the borylation of many (hetero)aromatic derivatives but show narrow applicability to azines (nitrogen-containing aromatic heterocycles), which are key components of many pharmaceutical and agrochemical products. Here we report an azine borylation strategy using stable and inexpensive amine-borane reagents. Photocatalysis converts these low-molecular-weight materials into highly reactive boryl radicals that undergo efficient addition to azine building blocks. This reactivity provides a mechanistically alternative tactic for sp carbon-boron bond assembly, where the elementary steps of transition-metal-mediated carbon-hydrogen bond activation and reductive elimination from azine-organometallic intermediates are replaced by a direct, Minisci-style, radical addition. The strongly nucleophilic character of the amine-boryl radicals enables predictable and site-selective carbon-boron bond formation by targeting the azine's most activated position, including the challenging sites adjacent to the basic nitrogen atom. This approach enables access to aromatic sites that elude current strategies based on carbon-hydrogen bond activation, and has led to borylated materials that would otherwise be difficult to prepare. We have applied this process to the introduction of amine-borane functionalities to complex and industrially relevant products. The diversification of the borylated azine products by mainstream cross-coupling technologies establishes aromatic amino-boranes as a powerful class of building blocks for chemical synthesis.
硼官能团常被引入以取代芳族碳氢键，从而通过分子片段的偶联加速小分子的多样化。目前基于过渡金属催化的碳氢键活化方法对许多（杂）芳族衍生物的硼化反应有效，但对嗪类（含氮芳族杂环）的适用性较窄，而嗪类是许多医药和农用化学品的关键成分。在此，我们报道了一种使用稳定且廉价的胺硼烷试剂的嗪硼化策略。光催化将这些低分子量材料转化为高活性的硼自由基，这些自由基能有效地加成到嗪结构单元上。这种反应性为sp碳 - 硼键组装提供了一种机制上不同的策略，其中过渡金属介导的碳氢键活化以及从嗪 - 有机金属中间体的还原消除的基本步骤被直接的、类似Minisci反应的自由基加成所取代。胺 - 硼自由基的强亲核特性通过靶向嗪的最活化位置，包括与碱性氮原子相邻的具有挑战性的位点，实现了可预测的和位点选择性的碳 - 硼键形成。这种方法能够实现目前基于碳氢键活化的策略难以触及的芳族位点，并得到了否则难以制备的硼化材料。我们已将此过程应用于将胺 - 硼烷官能团引入复杂且与工业相关的产品中。通过主流交叉偶联技术对硼化嗪产物进行多样化，确立了芳族氨基硼烷作为一类强大的化学合成结构单元。
