Direct Approaches to Nitriles via Highly Efficient Nitrogenation Strategy through C–H or C–C Bond Cleavage

• Published in: Accounts of chemical research 2014-04, Vol.47 (4), p.1137-1145
• Main Authors: Wang, Teng, Jiao, Ning
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Azides (organic); Bonding; Carbon - chemistry; Carbon-carbon composites; Chemistry Techniques, Synthetic; Cleavage; Hydrocarbons; Imines - chemistry; Nitriles; Nitriles - chemical synthesis; Nitriles - chemistry; Oxygen - chemistry; Strategy; Synthesis (chemistry)
• ISSN: 0001-4842; 1520-4898
• DOI: 10.1021/ar400259e

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 Csp3 –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.