Microwave-enhanced additive-free C-H amination of benzoxazoles catalysed by supported copper

Abstract

The C2-amination of benzoxazole offers wide-ranging potential for substrate expansion and the functionalisation of bioactive compounds. This study presents a green and efficient C-H amination, catalysed by CuCl and CuCl₂, in acetonitrile without acidic, basic or oxidant additives that is accelerated by microwave (MW) irradiation and is completed in 1.5-2 h. A solid Cu(I) catalyst supported on aminated silica made the process cost-effective and heterogeneous, thus simplifying work-up and minimising free copper in solution. The catalyst was found to be regeneratable and reusable for up to eight cycles. The optimised method facilitated the synthesis of various benzoxazole derivatives, demonstrating its versatility and practical applicability.

Keywords: aerobic oxidation; copper; grafted silica; heterogeneous catalysis; microwave.

Scheme 1

Representative synthetic routes for the C–H amination of benzoxazole using supported copper catalysts.

Figure 1

Reaction of benzimidazole with piperidine. a) Reaction scheme including intermaidates and b) conversion and selectivity plot of the C2-amination of benzoxazole with piperidine. Reaction conditions: benzoxazole (0.1 mmol), piperidine (0.15 mmol), copper catalyst, solvent (1.0 mL). Conversion was measured by NMR spectroscopy (see Figure S1 in Supporting Information File 1 for an example).

Figure 2

Reaction rate comparison between conventional (oil bath) and MW heating. Reaction conditions: benzoxazole (0.1 mol), piperidine (0.15 mmol), copper catalyst 20 mol %, solvent (1.0 mL). Conversion was measured by ¹H NMR spectroscopy.

Scheme 2

Graphical representation of Si-MonoAm-Cu(I) and Si-DiAm-Cu(I) preparation.

Figure 3

TGA profiles of SIPERNAT silica and Si-MonoAm and Si-DiAm.

Scheme 3

Scope of the MW-promoted C2-amination of benzoxazole catalysed by Si-MonoAm-Cu(I). Reaction conditions: benzoxazole (1.0 mmol), amine (2 mmol), Cu(I) catalyst (0.2 mmol), acetonitrile (1 mL), MW 80 °C, 2 h, 5 bar air; yields refer to isolated compounds.

Scheme 4

C2-Amination of substituted benzoxazoles. Reaction conditions: benzoxazole (1.0 mmol), piperidine (2 mmol), Cu(I) catalyst (0.2 mmol), acetonitrile (1 mL), MW 80 °C, 2 h, 5 bar air; yields refer to solated compounds.

Figure 4

Hot filtration test for the Si-MonoAm-Cu(I)-catalysed C2-amination of benzoxazole with piperidine in acetonitrile at 80 °C. Si-MonoAm-Cu(I) was filtered off after 60 min using a hot filter.

Figure 5

FTIR spectra of samples on the left 3800–2400 cm⁻¹ wavenumber on the right 1750–1350 cm⁻¹ wavenumber; a) Si-MomoAm, b) 5% Si-MonoAm-Cu(I), c) Si-MonoAm-Cu-used and d) 5% Si-MomoAm-Cu(II).

Figure 6

Si-MonoAm-Cu(I) catalyst reuse.

Figure 7

FESEM images of sample a) Si-MonoAm-Cu(I) 5 wt % and c) Si-MonoAm-Cu(I) 5 wt % used.

Figure 8

EDS maps of a) Si-MonoAm-Cu(I) and b) Si-MonoAm-Cu(I) used.