State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University , Xue Yuan Rd. 38, Beijing 100191, China.
Acc Chem Res. 2014 Apr 15;47(4):1137-45. doi: 10.1021/ar400259e. Epub 2014 Mar 31.
Because of the importance of nitrogen-containing compounds in chemistry and biology, organic chemists have long focused on the development of novel methodologies for their synthesis. For example, nitrogen-containing compounds show up within functional materials, as top-selling drugs, and as bioactive molecules. To synthesize these compounds in a green and sustainable way, researchers have focused on the direct functionalization of hydrocarbons via C-H or C-C bond cleavage. Although researchers have made significant progress in the direct functionalization of simple hydrocarbons, direct C-N bond formation via C-H or C-C bond cleavage remains challenging, in part because of the unstable character of some N-nucleophiles under oxidative conditions. The nitriles are versatile building blocks and precursors in organic synthesis. Recently, chemists have achieved the direct C-H cyanation with toxic cyanide salts in the presence of stoichiometric metal oxidants. In this Account, we describe recent progress made by our group in nitrile synthesis. C-H or C-C bond cleavage is a key process in our strategy, and azides or DMF serve as the nitrogen source. In these reactions, we successfully realized direct nitrile synthesis using a variety of hydrocarbon groups as nitrile precursors, including methyl, alkenyl, and alkynyl groups. We could carry out C(sp(3))-H functionalization on benzylic, allylic, and propargylic C-H bonds to produce diverse valuable synthetic nitriles. Mild oxidation of C═C double-bonds and C≡C triple-bonds also produced nitriles. The incorporation of nitrogen within the carbon skeleton typically involved the participation of azide reagents. Although some mechanistic details remain unclear, studies of these nitrogenation reactions implicate the involvement of a cation or radical intermediate, and an oxidative rearrangement of azide intermediate produced the nitrile. We also explored environmentally friendly oxidants, such as molecular oxygen, to make our synthetic strategy more attractive. Our direct nitrile synthesis methodologies have potential applications in the synthesis of biologically active molecules and drug candidates.
由于含氮化合物在化学和生物学中的重要性，有机化学家长期以来一直专注于开发其合成的新方法。例如，含氮化合物出现在功能材料、畅销药物和生物活性分子中。为了以绿色和可持续的方式合成这些化合物，研究人员专注于通过 C-H 或 C-C 键断裂直接官能化烃。尽管研究人员在简单烃的直接官能化方面取得了重大进展，但通过 C-H 或 C-C 键断裂直接形成 C-N 键仍然具有挑战性，部分原因是一些 N-亲核试剂在氧化条件下不稳定。腈是有机合成中用途广泛的构建块和前体。最近，化学家们在化学计量金属氧化剂的存在下，用有毒的氰化物盐实现了直接 C-H 氰化。在本综述中，我们描述了我们小组在腈合成方面的最新进展。C-H 或 C-C 键断裂是我们策略中的关键过程，叠氮化物或 DMF 用作氮源。在这些反应中，我们成功地使用各种烃基作为腈前体，包括甲基、烯基和炔基，直接合成腈。我们可以对苄基、烯丙基和炔丙基 C-H 键进行 C(sp(3))-H 官能化，生成各种有价值的合成腈。C═C 双键和 C≡C 三键的温和氧化也产生了腈。氮通常掺入碳骨架中，涉及叠氮试剂的参与。尽管一些机理细节尚不清楚，但这些氮化成反应的研究表明涉及阳离子或自由基中间体，并且叠氮化物中间体的氧化重排生成腈。我们还探索了环境友好的氧化剂，如分子氧，以使我们的合成策略更具吸引力。我们的直接腈合成方法在生物活性分子和药物候选物的合成中有潜在的应用。
