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Synlett 2009(4): 628-632  
DOI: 10.1055/s-0028-1087915
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Sankar K. Guchhait*, Chetna Madaan
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S. A. S. Nagar (Mohali)-160062, Punjab, India
Fax: +91(172)2214692; e-Mail: skguchhait@niper.ac.in;
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Publication History

Received 3 November 2008
Publication Date:
16 February 2009 (online)

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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

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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.