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Iron-Catalyzed Anti-Markovnikov Hydroamination and Hydroamidation of Allylic Alcohols
- Ma, Wei, Zhang, Xiaohui, Fan, Juan, Liu, Yuxuan, Tang, Weijun, Xue, Dong, Li, Chaoqun, Xiao, Jianliang, Wang, Chao
- Journal of the American Chemical Society 2019 v.141 no.34 pp. 13506-13515
- alcohols, amines, amino acids, catalytic activity, dehydrogenation, drugs, heterocyclic compounds, hydrogenation, iron, moieties, organocatalysts, solvents, stereochemistry
- Hydroamination allows for the direct access to synthetically important amines. Controlling the selectivity of the reaction with efficient, widely applicable, and economic catalysts remains challenging, however. This paper reports an iron-catalyzed formal anti-Markovnikov hydroamination and hydroamidation of allylic alcohols, which yields γ-amino and γ-amido alcohols, respectively. Homoallylic alcohol is also feasible. The catalytic system, consisting of a pincer Fe-PNP complex (1–4 mol %), a weak base, and a nonpolar solvent, features exclusive anti-Markovnikov selectivity, broad substrate scope (>70 examples), and good functional group tolerance. The reaction could be performed at gram scale and applied to the synthesis of drug molecules and heterocyclic compounds. When chiral substrates are used, the stereochemistry and enantiomeric excess are retained. Further application of the chemistry is seen in the functionalization of amino acids, natural products, and existing drugs. Mechanistic studies suggest that the reaction proceeds via two cooperating catalytic cycles, with the iron complex catalyzing a dehydrogenation/hydrogenation process while the amine substrate acts as an organocatalyst for the Michael addition step.