A New Approach to the Synthesis of 2-Aminoimidazo[1,2-a]pyridine
Derivatives Through Rapid Parallel Synthesis

Abstract

Different substituted 6-(2,6-difluorobenzoyl)-imidazopyridines 3 have been prepared using rapid parallel synthesis. Key cyanamide intermediate 4 was prepared from chloropyridine 1, and alkylated at the endocyclic nitrogen with different bromoacetophenones (prepared also in rapid parallel synthesis fashion). Subsequent cyclization was performed in situ with EtOAc/H₂O to give target molecules.

rapid parallel synthesis - imidazopyridine - antiviral agents - heterocycle - cyclization

References

1 Bonnet PA. Michael A. Laurent F. Sablayrolles C. Rechencq E. Mani JC. Boucard M. Chapat JP. J. Med. Chem.  1992,  35:  3353 ; and references cited therein

2 Ezquerra-Carrera J, Hamdouchi C, Gruber JM, Homes RE, and Spitzer WA. inventors; WO  99/59587. 

3 Montgomery JA. Secrist AA. In Comprehensive Heterocyclic Chemistry   Katritzky AR. Pergamon; Oxford: 1984.  Chap. 4.10. p.607 ; and references cited therein

4 Vega JA. Vaquero JJ. Alvarez-Builla J. Ezquerra J. Hamdouchi C. Tetrahedron  1999,  55:  2317 

5a Hamdouchi C. de Blas J. del Prado M. Gruber J. Heinz BA. Vance L. J. Med. Chem.  1999,  42:  50 

5b Hamdouchi C. Sanchez C. Ezquerra J. Synthesis  1998,  867 

6

General Procedure : A solution of cyanamide (1.89 g, 45 mmol, 1.5 equiv) in DMF (50 mL) was treated with NaH (60% mineral oil, 3.84 g, 96 mmol, 3.2 equiv) at 0 ºC, and the suspension was stirred at r.t. for 45 min. A solution of chloropyridine 5 (7.6 g, 30 mmol) in DMF (75 mL) was then slowly added at 0 ºC and the resulting mixture was stirred at r.t. for 2.5 h. After this time, methanol (20 mL) was slowly added at 0 ºC and the suspension was filtered through a pad of SiO₂ (ethyl acetate:ethyl acetate/methanol 1:1) to give cyanimide 6, which was used without further purification.
To a solution of 6 (0.87 M in DMF, 1 mmol scale) was added a solution of 7 (3.1 M in DMF, 2.5 equiv) and diisopropyl-ethylamine (6 equiv), and the mixture was vigorously stirred at r.t. for 4 h. Then, H₂O (4 mL/mmol) and EtOAc (4 mL/mmol) were successively added, and the stirring was continued at r.t. for 18 h. The mixture was then diluted with H₂O (15 mL/mmol) and extracted with EtOAc (3 × 15 mL/mmol), and the combined organic layers were washed with H₂O (10 mL/mmol) and concentrated under vacuum. The residue was purified by automated HPLC-MS to give 8 (4-28% overall yield, >95% purity). Compound 8a: ¹H NMR (d ₆-acetone, 500 MHz): δ = 9.43 (br s, 1 H, CH), 8.00 (dd, J = 1.9 Hz, 9.1 Hz, 1 H, CH), 7.70 (ddd, J = 6.6 Hz, 8.2 Hz, 8.5 Hz, 1 H, CH), 7.60 (m, 2 H, 2 CH), 7.52 (m, 3 H, 3 CH), 7.47 (d, J = 9.4 Hz, CH), 7.21 (dd, J = 7.8 Hz, 8.2 Hz, 2 H, 2 CH), and 5.85 (br s, 2 H, NH₂) ppm. ¹³C NMR (d ₆-acetone, 125 MHz): δ = 185.7, 184.0, 161.0, 160.3, 149.7, 141.1, 134.6, 134.0, 132.0, 130.0,128.9, 127.8, 124.1, 116.9, 115.1, 113.2, 108.2 ppm.

7a The acetophenones not commercially available were prepared by condensation of an aryllithium derivative with acetaldehyde. See, for example: Soll RM. Guinosso C. Asselin A. J. Org. Chem.  1988,  53:  2844 ; and further oxidation with tetra-n-propylammonium perruthenate (Pr₄N⁺RuO₄ ^-)

7b For a review, see: Ley SV. Norman J. Griffith WP. Marsden SP. Synthesis  1994,  639 

8 Arrieta A. Ganboa I. Palomo C. Synth. Commun.  1984,  14:  939