Mechanistic and Computational Insights into Asymmetric Intramolecular Iron-Catalyzed Nitrene Transfer into Benzylic C─H Bonds

Abstract

Chiral, nonracemic amines are valuable synthetic building blocks for diverse bioactive molecules. Asymmetric C─H amination via transition metal-catalyzed nitrene transfer (NT) is a popular strategy to access enantioenriched benzylamines, but many useful chemocatalysts for this transformation are based on precious metals or require elaborate ligands. Iron catalysts supported by simple ligands capable of asymmetric aminations of diverse sulfamates would be valuable but are surprisingly rare. Herein, we study features of the asymmetric iron-catalyzed NT of homo- and bis-homobenzylic sulfamates to better understand why the development of such reactions has proven challenging. Diverse parameters were examined, including ligand, iron source, oxidant, additive, and solvent. Reactions of the preoxidized iminoiodinane revealed some unexpected relationships between the pK _a of acid additives and the enantiomeric ratio (er). Computational models show that radical rebound is the enantiodetermining step and highlight noncovalent interactions (NCIs) between the ligand and aryl ring of the substrate that drive the er. These insights, combined with experimental data, provide a foundation for the design of second-generation chemocatalysts for iron-catalyzed asymmetric C─H amidation via NT.

Keywords: C─H functionalization; Iron; amidation; asymmetric; nitrene transfer.

Figure 1.

Hydrogen atom transfer transition states with different Fe─nitrenoid complexes. All Gibbs free energies are in kcal/mol, with respect to the most stable Fe─nitrenoid complex 7.

Figure 2.

Computed reaction free energy profiles of the Fe-catalyzed asymmetric intramolecular nitrene transfer with an L3-supported Fe catalyst.

Figure 3.

Enantioselectivity-determining radical rebound transition states and ligand effects on enantioselectivity.

Scheme 1.. Reported Fe-Based Chemocatalysts for Asymmetric C─H Nitrene Transfer

Scheme 2.. Scope for Asymmetric Iron-Catalyzed Amination of Benzylic C─H Bonds^a

^a Procedure: A solution of Fe(OTf)₂ (10 mol%) and L3 (15 mol%) with 4 Å MS (50 mg) and 1 (0.100 mmol, 1 equiv) in MeCN (total concentration of 0.05 M) was treated with PhI(OPiv)₂ (1.2 equiv). The reaction mixture was stirred at 25 °C for 18 h. ^bIsolated yield. ^cDetermined by HPLC analysis.^dAbsolute stereochemistry was determined by obtaining an X-ray crystal structure of 2d (see the ^SI). ^eDetermined by crude NMR. ^frac-L3 was used. ^gMinor diastereomer was not observed. ^h53% crude NMR yield with 77:23 er when L8 was used instead of L3.

Scheme 3.. Investigation on Oxidant Effect via Fe Catalysis with Iminoiodinane

^aThe Fe salt (10 mol%), L3 (15 mol%), 4 Å MS (50 mg), and the acid additive (0–1 equiv) in MeCN were treated with iminoiodinane (1 equiv, 0.100 mmol) at 25 °C for 18 h. ^bIn situ generated with Fe(L3)Cl₂ (10 mol%) and AgOPiv (20 mol%). ^cCrude NMR yield determined with 1,3,5-trimethylbenzene as the internal standard. ^dDetermined by HPLC analysis. ^e38% isolated yield. ^fFe(OTf)₂ was used. ^g74% isolated yield.

Scheme 4.. Mechanistic Investigations

^aDetermined by crude ¹H NMR using mesitylene as the internal standard. ^bIndicated yields are isolated yields.

Scheme 5.. Intra- and Intermolecular KIE Experiments

^aee was determined by molecular rotational resonance spectroscopy. ^bDetermined by crude NMR with 1,3,5-trimethylbenzene as internal standard. ^cAverage isolated yield. ^dee was based on [D]1-1a. ^eConversion was determined based on D-labeled sulfamate obtained by decomposition of D-labeled iminoiodinane.