Chiral amines are core structural motifs in pharmaceuticals (present in 40-45% of small-molecule drugs), agrochemicals, and natural products. Traditional synthetic methods, such as racemate resolution or asymmetric hydrogenation of imines, often require pre-functionalized substrates or the use of high-pressure hydrogen/stoichiometric reagents, resulting in low atom economy. The borrowing hydrogen strategy offers a greener alternative via a catalytic oxidation-condensation-reduction cascade, using alcohols as the hydrogen source. This approach avoids intermediate isolation and external oxidants/reductants, generating only water as a byproduct. While iron is an abundant, cheap, and biocompatible metal, its use in enantioconvergent amination of secondary alcohols remained unreported. The collaborative team of Prof. Weiping Liu and Prof. Bolin Ji (Donghua University) and Prof. Shaofei Ni (Shantou University) has now achieved this transformation. By employing a chiral phosphoric acid (CPA)​ as an external chiral inducer, they realized the iron-catalyzed enantioconvergent amination of racemic secondary alcohols with amines (Figure 1).

The authors initiated their study using 1-phenylethanol (1a) and aniline (2a) as benchmark substrates (Figure 2). Screening various chiral phosphoric acids in the presence of a (cyclopentadienone)iron complex (Fe-1) as catalyst, trimethylamine N-oxide, and 4 Å molecular sieves in toluene revealed a significant influence of steric bulk at the 2,6-positions of the CPA's phenyl group on both yield and enantioselectivity. Introducing 2,4,6-tricyclopentyl (CPA-5) or 2,4,6-tricyclohexyl (CPA-6) substituents improved performance, with 2,4,6-triisopropyl substitution (CPA-7) affording the target product in 82% yield and 81% ee. After identifying CPA-7​ as the optimal chiral acid, reaction conditions were further optimized. Evaluation of various iron catalysts (Fe-1​ to Fe-5) combined with CPA-7​ aimed to enhance efficiency and selectivity (Figure 2B). Control experiments confirmed the indispensability of both components: no reaction occurred without the iron catalyst, and only trace product formed in the absence of CPA, highlighting their synergistic effect. Solvent screening indicated a preference for low-polarity solvents. Toluene and ethylbenzene showed similar efficiency, while mesitylene and o-xylene performed even better. By adjusting catalyst loadings, temperature, concentration, and time, the target amination product was successfully obtained in 98% yield and 95% ee.

With optimal conditions established, the scope of aniline substrates 2​ was explored (Figure 3). A variety of chiral amines were synthesized in good to excellent yields with high enantioselectivity, demonstrating remarkable functional group tolerance. ortho-Methylaniline (4) led to slightly reduced yield and ee due to steric hindrance. meta-substituted anilines, para-halogenated anilines (5-14), and anilines bearing strong electron-withdrawing groups (15-18) reacted in high to moderate yields while maintaining excellent ee. Aromatic amines like 3,5-dimethylaniline (20) and heterocyclic anilines (23-31) were also compatible. X-ray crystallography of product 29​ confirmed the Rconfiguration. Investigation of secondary alcohol substrates showed good performance for halogen-substituted aryl alcohols. Aliphatic secondary alcohols provided high yields but with moderate enantioselectivity. The system exhibited excellent compatibility with amino acids and peptides, affording products from amino acid, dipeptide, and tripeptide-derived substrates with high ee values.

DFT calculations indicate the reaction follows a borrowing hydrogen pathway, with all intermediates and transition states in the singlet state (Figure 4). Key steps include iron catalyst activation, alcohol oxidation to ketone, imine formation, and hydrogen transfer. The chiral phosphoric acid interacts with the imine intermediate via hydrogen bonding. The significant steric bulk of its 2,4,6-triisopropyl substituents creates an energy difference of 3.8 kcal/mol between the diastereomeric transition states TS4​ and TS4-1, which dictates the excellent enantioselectivity. The larger dihedral angle in the Fe-1​ complex (104.3°) compared to Fe-4​ (31.3°) forms a more constrained catalytic pocket. This, combined with stabilizing C-H···π interactions, preferentially stabilizes the favored transition state and controls the product configuration. The computational results are consistent with experimental observations, clarifying the decisive role of the chiral environment in controlling selectivity.

This study developed an iron-catalyzed, CPA-mediated borrowing hydrogen strategy for the enantioconvergent amination of secondary alcohols with anilines. The method features a broad substrate scope and excellent functional group tolerance, enabling efficient synthesis of chiral amines. Its compatibility with peptides and tolerance towards halogens, cyano, ester, NH-free amino, and alkene groups provide handles for further functionalization. Mechanistic studies confirm the borrowing hydrogen process, and DFT calculations elucidate the critical role of the chiral environment in controlling enantioselectivity.

Authors: Fan Sun, Bo-Xuan Yao, Siyi Wang, Bolin Ji, Shao-Fei Ni, and Weiping Liu

Title: Iron-Catalyzed Enantioconvergent Amination of Alcohols

Journal: Journal of the American Chemical Society (JACS)

DOI: 10.1021/jacs.5c07101