Fast Assembly of 1H-Imidazo[1,2-a]imidazol-5-amines via Groebke–Blackburn–Bienaymé Reaction with 2-Aminoimidazoles

Abstract

A novel microwave-assisted protocol allowing the ­successful application of 2-aminoimidazoles in the Groebke–­Blackburn–Bienaymé reaction for the facile construction of the 1H-imidazo[1,2-a]imidazol-5-amine core was developed.

Key words

multicomponent reactions - annulation - heterocycles - fused-ring systems

• References and Notes

• 1 The authors contributed equally to this work.

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• 12 Microwave-Assisted Groebke–Blackburn–Bienaymé Reaction; Typical Procedure for 1-Benzyl-N-tert-butyl-2,6-diphenyl-1H-imidazo[1,2-a]imidazol-5-amine (4a): To a microwave vial equipped with a magnetic stir bar containing 1a (75 mg, 0.3 mmol) and p-toluenesulfonic acid hydrate (11 mg, 0.06 mmol), anhydrous toluene (1 mL), 2a (38 mg, 0.36 mmol) and 3a (37 mg, 0.45 mmol) were consecutively added. The reaction vessel was sealed and irradiated in the cavity of a CEM-Discover microwave reactor at a set temperature of 110 °C for 30 min. Upon completion of the reaction, the vial was cooled with a stream of air. The resulting reaction mixture was diluted with EtOAc (50 mL), thoroughly washed with 1 M HCl (2 × 50 mL) and sat. aq Na₂CO₃ (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was dissolved in EtOAc (5 mL) and subjected to flash chromatography [silica (25 g); EtOAc–heptane, 3:7] to give pure 4a (87 mg, 69%). ¹H NMR (300 MHz, CDCl₃): δ = 8.07–7.95 (m, 2 H), 7.41–7.26 (m, 7 H), 7.25–7.10 (m, 6 H), 6.94 (s, 1 H), 5.22 (s, 2 H), 2.90 (br s, 1 H), 1.12 (s, 9 H); ¹³C NMR (CDCl₃, 75 MHz): δ = 145.5, 137.4, 136.3, 136.2, 133.3, 129.5, 128.9, 128.7, 128.62, 128.56, 128.47, 128.0, 127.4, 127.3, 126.0, 120.1, 102.5, 55.6, 47.0, 30.3; HRMS (EI): m/z calcd for C₂₈H₂₈N₄: 420.2314; found: 420.2281.
• 13 CAUTION! The acidic aqueous workup was necessary in most cases to decompose imine 5, which was otherwise difficult to separate from the desired product 4 (Scheme 1). See the Supporting Information for details.