Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide-alkyne cycloaddition

Abstract

A novel catalyst-free synthetic approach to 1,2,3-triazolobenzodiazepinones has been developed and optimized. The Ugi reaction of 2-azidobenzaldehyde, various amines, isocyanides, and acids followed by microwave-assisted intramolecular azide-alkyne cycloaddition (IAAC) gave a series of target heterocyclic compounds in moderate to excellent yields. Surprisingly, the normally required ruthenium-based catalysts were found to not affect the IAAC, only making isolation of the target compounds harder while the microwave-assisted catalyst-free conditions were effective for both terminal and non-terminal alkynes.

Keywords: Ugi reaction; click chemistry; microwave chemistry; multicomponent reactions; triazolobenzodiazepines.

Figure 1

Benzodiazepine-based azolo-containing drugs.

Figure 2

Novel potential 1,2,3-triazolobenziadiazepine drugs.

Scheme 1

Examples of synthesis of 1,2,3-triazolobenzodiazepines via tandem approach Ugi reaction/IAAC. Reagents and conditions: (a) MeOH, reflux, 24 h; (b) (1) 4 Å MS, EtOH, rt, 20 h, (2) Base, rt, 30 min, (3) EtOH, reflux, 3 h; (c) (1) MeOH, 24–48 h, rt, (2) PhH, reflux, 4–18 h; (d) (1) MeOH, rt, 8 h; (2) NaN₃, CuI, ʟ-proline, DMSO, 120 °C, 24 h; (e) (1) MeOH, rt, 24 h, (2) NaN₃, CuI, DMSO, 100 °C, 3 h.

Scheme 2

Azide precursor synthesis.

Scheme 3

Synthesis of Ugi products 6, their structures and yields.

Figure 3

Code legend for Ugi products 6 and molecular structure (X-ray analysis) of compound 6aaa.

Scheme 4

Cyclization of Ugi-product 6aab with terminal alkyne fragment.

Figure 4

¹H NMR spectra of the reactant and the product of IAAC.

Figure 5

Molecular structure of compound 7aaa (X-ray analysis) and comparison of ¹H NMR spectra of compounds 6aaa and 7aaa.

Scheme 5

The substrate scope of intermolecular cycloaddition.