Discovery of a simple iron catalyst reveals the intimate steps of C-H amination to form C-N bonds

Abstract

Formation of ubiquitous C-N bonds traditionally uses prefunctionalized carbon precursors. Recently, metal-catalyzed amination of unfunctionalized C-H bonds with azides has become an attractive and atom-economic strategy for C-N bond formation, though all catalysts contain sophisticated ligands. Here, we report Fe(HMDS)₂ (HMDS = N(SiMe₃)₂ ^-) as an easy-to-prepare catalyst for intramolecular C-H amination. The catalyst shows unprecedented turnover frequencies (110 h^-1 vs. 70 h^-1 reported to date) and requires no additives. Amination is successful for benzylic and aliphatic C-H bonds (>80% yield) and occurs even at room temperature. The simplicity of the catalyst enabled for the first time comprehensive mechanistic investigations. Kinetic, stoichiometric, and computational studies unveiled the intimate steps of the C-H amination process, including the resting state of the catalyst and turnover-limiting N₂ loss of the coordinated azide. The high reactivity of the iron imido intermediate is rationalized by its complex spin system revealing imidyl and nitrene character.

Fig. 1. Time–conversion profiles for the C–H amination to yield 1b using different initial concentrations of substrate 1a. Inset displays the linear dependence of initial rates on the initial substrate concentration. See the ESI for experimental details.

Fig. 2. Time–conversion profiles for the formation of 1b using different catalyst concentrations (4.5 mM–17.9 mM) and 0.11 M 1a. Inset displays the independence of catalyst concentration on the initial reaction rates. See the ESI for experimental details.

Fig. 3. Time-dependent yield of 1b and 1b–d₂ from intermolecular KIE competition experiments.

Fig. 4. Evolution of C–H amination product 1b from azide 1a (red trace), 1a–d₂ (blue trace), and a 1 : 1 mixture of the two substrates (black trace).

Fig. 5. (a) Stoichiometric reaction of substrate 1a with Fe(HMDS)₂; (b) ¹H NMR spectra of the reaction with Fe(HMDS)₂ with different equivalents of substrate 1a at t = 0 in C₆D₆; (c) FTIR-spectra of substrate 1a (black) and a mixture (1 : 1) of 1a and Fe(HMDS)₂ at t = 0 (red) and after 24 h (blue).

Fig. 6. FTIR spectra of a mixture of substrate 1a and Fe(HMDS)₂ at t = 0 using 0.5, 1.0 and 2.0 equivalents of 1a; free azide at 2099 cm⁻¹, azide of 2 at 2118 cm⁻¹.

Fig. 7. ¹H NMR spectra of the reaction of Fe(HMDS)₂ with different equivalents of substrate 1a at t = 24 h in C₆D₆.

Fig. 8. ORTEP representation of 4 (50% probability ellipsoids, all carbon-bound H atoms omitted for clarity).

Scheme 1. Reaction coordinate profile of the proposed mechanism for the intramolecular C–H amination catalyzed by Fe(HMDS)₂. Energies calculated by DFT are giving in kcal mol⁻¹ (see Fig. S27–S40 for structures of optimized intermediates and transition states).

Fig. 9. Ball and stick representation of the optimized transition state TS-i3/i4 by DFT (B3LYP/def2-TZVP) in the pentet spin state. H atoms on all carbons omitted for clarity (Fe orange, N blue, Si mint, C grey, H off-white).

Fig. 10. Active space orbitals from a NEVPT2-CASSCF(10,8) calculation on gauche-i3. Orbital filling of the main contribution (55%) is illustrated. Partial occupation due to multi-reference character described in brackets per orbital. Isosurface is set at 90. All Me groups omitted for clarity.