Iron-Catalyzed Anti-Markovnikov Hydroamination and Hydroamidation of Allylic Alcohols Wei Ma, † Xiaohui Zhang, † Juan Fan, † Yuxuan Liu, † Weijun Tang, † Dong Xue, † Chaoqun Li, † Jianliang Xiao,* ,†,‡ and Chao Wang* ,† † Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an, 710062, China ‡ Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, U.K. * S Supporting Information ABSTRACT: 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. ■ INTRODUCTION Hydroamination of alkenes is a direct, atom-economic approach to accessing amines, the most ubiquitous function- alities found in fine chemicals, pharmaceuticals, and agro- chemicals (Figure 1a). 1 As such, it has been extensively studied over the past two decades or so, expanding into a wide variety of amines and alkenes. 2 Rather surprisingly, however, examples of hydroamination of allylic alcohols are rare. Allylic alcohol is a readily available commodity chemical. 3 Bearing a hydroxy and olefinic functionality, allyl alcohol and the derivatives have been used as an intermediate in various chemical syntheses. Hydroamination of the CC double bonds of allylic alcohols would generate highly valuable β- 4 or γ- 5 amino alcohols, depending on the reaction being Markovnikov or anti- Markovnikov selective. To the best of our knowledge, however, there appears to be no example of Markovnikov hydroamination of allylic alcohols in the literature, and only one report on anti- Markovnikov hydroamination is known, which, catalyzed by a Ru complex, proceeds via a hydrogen-borrowing process, accord- ing to Oe and co-workers 6 (Figure 1b). Herein, we disclose the first examples of iron-catalyzed hydroamination of allylic alcohols with exclusive anti-Markovnikov selectivity to produce γ-amino alcohols. The hitherto unprecedented hydroamidation of allylic alcohols is also demonstrated (Figure 1c). Hydroamination of terminal alkenes normally affords products with Markovnikov selectivity. 2 While significant advances have been made in anti-Markovnikov hydroamina- tion in the past few years, controlling the selectivity remains challenging, due to the intrinsic electronic and steric bias embedded in the reacting alkene and amine substrates. 7 Notable strategies in directing the amination in the anti- Received: May 15, 2019 Published: August 6, 2019 Figure 1. Hydroamination of alkenes and Fe-catalyzed formal anti- Markovnikov hydroamination/hydroamidation of allyl alcohols. Article pubs.acs.org/JACS Cite This: J. Am. Chem. Soc. 2019, 141, 13506-13515 © 2019 American Chemical Society 13506 DOI: 10.1021/jacs.9b05221 J. Am. Chem. Soc. 2019, 141, 13506-13515 Downloaded via UNIV OF LIVERPOOL on August 2, 2020 at 10:49:56 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.