An Efficient, Regioselective, Versatile Synthesis of N-Fused 2- and 3-Aminoimidazoles via Ugi-Type Multicomponent Reaction Mediated by Zirconium(IV) Chloride in Polyethylene Glycol-400

Abstract

An Ugi-type multicomponent reaction of heterocyclic amidines with aldehydes and isocyanides catalyzed by zirconium(IV) chloride in PEG-400 was developed. The protocol offers the rapid, environment friendly, regioselective and versatile synthesis of medicinally important N-fused 2- and 3-aminoimidazoles in good to high yields. The combination of catalyst and solvent, that was judiciously explored, was crucial for regioselectivity and versatility of the method.

Key words

multicomponent reaction - regioselective synthesis - N-heterocycles - zirconium(IV) chloride - polyethylene glycol

References and Notes

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18

Representative Experimental Procedure for the Synthesis of N - tert -Butyl-2-(4-chlorophenyl)imidazo[1,2- a ]pyridin-3-amine (Table 2, entry 1): To a mixture of 2-aminopyridine (0.19 g, 2 mmol) and 4-chlorobenzaldehyde (0.28 g, 2 mmol) in PEG-400 (2 mL), tert-butyl isocyanide (0.17 g, 2 mmol) and ZrCl₄ (47 mg, 10 mol%) were added. The mixture was allowed to stir at 50 ˚C under open air. After completion of the reaction (4.5 h, monitored by TLC), the resulting mixture was extracted with EtOAc and washed with H₂O. The organic layer was dried over anhyd Na₂SO₄, filtered and concentrated under reduced pressure. The column chromatographic purification of crude product over silica gel (mesh size: 60-120) eluting with EtOAc-hexane (1:1.5) afforded N-tert-butyl-2-(4-chlorophenyl)imidazo-[1,2-a]pyridin-3-amine (0.48 g, 85%); white solid; mp 146-149 ˚C. MS (ESI): m/z = 300 [M + 1]. ^¹H NMR (400 MHz, CDCl₃): δ = 1.06 (s, 9 H), 3.00 (br, NH), 6.78 (t, J = 6.8 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.54 (d, J = 7.2 Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 8.20 (d, J = 6.8 Hz, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 30.3 (3 × Me), 56.4 (C), 111.5 (CH), 117.3 (CH), 123.3 (CH), 123.4 (C), 124.3 (CH), 128.4 (2 × CH), 129.3 (2 × CH), 133.1 (C), 133.7 (C), 138.3 (C), 142.0 (C). IR (KBr): 3457, 2972, 1635, 1194, 770 cm^-¹. Anal. Calcd for C₁₇H₁₈ClN₃: C, 68.11; H, 6.05; N, 14.02. Found: C, 67.89; H, 6.07; N, 13.99.
All reactions (Tables  [¹] -  [³] ) were carried out following this procedure.