金属催化惰性C(sp3)-H键的定位选择性功能化研究

Unactivated sp3 C−H bonds are ubiquitously present in medicinal compounds and biologically active natural products. Site-selective catalytic functionalization of these naturally inert strong bonds offers a simple and efficient tool for the construction of C–C bonds in synthetic organic and medicinal chemistry. A number of impressing catalytic processes have been discovered over the last ten years using ligand-directed cross coupling as a strategy. However, current studies are predominantly relied on the use of the precious palladium salts as catalysts with a limited reaction scope. Moreover, direct sp3 C−H addition to polar bonds has not been achieved, mainly due to the weak nucleophilicity of the sp3 C−M bonds generated in situ from metal-promoted C−H bond activation..The objective of this proposed research is to develop unprecedented site-selective sp3 C−H bond processes of simple aliphatic amides with abundant, inexpensive, and environmentally friendly cobalt salts as the catalysts based on the following observations. First, low rates of β-hydride elimination are often observed with alkylcobalt species as compared to other alkylmetal counterparts such as the palladium species, enabling the development of complementary processes to palladium catalysis. Second, cobalt salts have a high affinity to unsaturated C−N, and C−O bonds, allowing them for the development of nucleophilic addition reactions. Third, cobalt catalysis often exhibits distinct reaction pathways from other metals, allowing for the development of novel processes specific to cobalt catalysts.

惰性sp3 C-H键普遍存在于药物以及活性天然产物中。在有机合成和药物化学中，金属催化的惰性的sp3 C-H键的位点选择性官能化成为C-C键构建的强有力工具。其中，金属催化配位导向的交叉偶联策略成为研究焦点。然而，目前此类研究主要依赖于钯催化剂的使用，但其适用范围受限。另一方面，由于金属促进的C-H键活化原位产生的sp3 C-M键的亲核性较弱，故sp3 C-H键与极性双键的直接加成到一直未实现。本项目拟使用丰富且价格低廉，环境友好的钴催化剂，研究新型的脂肪酰胺位点选择性的sp3 C-H键活化，基于以下事实：1）芳基钴物种与其它芳基金属物种如钯物种相比较，在发生β-氢消除时速率较低，可对钯催化反应进行补充；2）钴盐对不饱和的C-N键和C-O键具有高亲和性，可发展亲核加成反应；3）钴催化反应常常经历与其它金属催化反应不同的反应历程，因此，可建立与众不同的钴催化反应.

芳香族和脂肪族化合物存在于有机、药物和材料化学的各个方面。在学术界和工业界中活化和功能化的化合物一直非常活跃且重要。特别是含有脂肪醛或胺基的化合物，已成为石油化工或化石原料常见的下游产品。这些分子作为产品的关键中间体或亚基，在农药、材料和医药工业中也具有重要意义。迄今为止，人们致力于直接官能化含醛和含胺碳氢化合物等惰性的芳香族和脂肪族C-H键，并取得了重大进展。在国家自然科学基金资助期间，我们通过寻找一系列催化剂和催化体系，实现了这些惰性和活性较差的芳香族和脂肪族C–H键位置选择性功能化。我们已经开发了芳香族和脂肪族醛及伯胺在有或没有瞬时导向基团的协助下，通过过渡金属催化的未活化sp2和sp3碳上的C–H键活化和官能化过程，直接的，高度选择性的形成C(sp3)-C(sp2), C(sp2)-C(sp2), C(sp3)O 与 CN键。原子和成本效益、可持续性，以及催化过程有望显著提高现有石油原料的结构和实用的价值，并将对有机、材料、药物化学和制药工业产生重大影响。