Article: Regiocontrolled microwave assisted bifunctionalization of 7,8-dihalogenated imidazo[1,2-a]pyridines: a one pot double-coupling approach

The reactivity of the 7-chloro-8-iodo- and 8-chloro-7-iodoimidazo[1,2-a]pyridines 1a-e diversely substituted on the 2 position, towards Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig cross-coupling reactions as well as cyanation was evaluated. Various methodologies are proposed to introduce aryl, heteroaryl, alkyne, amine or cyano groups in the two positions depending on the nature of the substituent present in position 2. In both series, the substitution of the iodine atom was totally regioselective and the difficulty was to substitute the chlorine atom in a second step. Until now, only hetero(aryl) groups could be introduced though Suzuki-Miyaura cross-coupling. We overcame this problem evaluating both regioisomers in parallel. The double coupling approach was also studied allowing the one pot Suzuki/Suzuki, cyanation/Sonogashira and cyanation/Buchwald reactions leading to polyfunctionnalized imidazo[1,2-a]pyridines.

Citing Articles

8-Aryl-6-chloro-3-nitro-2-(phenylsulfonylmethyl)imidazo[1,2-a]pyridines as potent antitrypanosomatid molecules bioactivated by type 1 nitroreductases.

Fersing C, Boudot C, Pedron J, Hutter S, Primas N, Castera-Ducros C Eur J Med Chem. 2018; 157:115-126.

PMID: 30092366 PMC: 7089781. DOI: 10.1016/j.ejmech.2018.07.064.

References

1.

Dahan-Farkas N, Langley C, Rousseau A, Yadav D, Davids H, de Koning C . 6-Substituted imidazo[1,2-a]pyridines: synthesis and biological activity against colon cancer cell lines HT-29 and Caco-2. Eur J Med Chem. 2011; 46(9):4573-83. DOI: 10.1016/j.ejmech.2011.07.036. View

2.

Trabanco A, Tresadern G, Macdonald G, Vega J, de Lucas A, Matesanz E . Imidazo[1,2-a]pyridines: orally active positive allosteric modulators of the metabotropic glutamate 2 receptor. J Med Chem. 2012; 55(6):2688-701. DOI: 10.1021/jm201561r. View

3.

Tresadern G, Cid J, Macdonald G, Vega J, de Lucas A, Garcia A . Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor. Bioorg Med Chem Lett. 2009; 20(1):175-9. DOI: 10.1016/j.bmcl.2009.11.008. View

4.

Enguehard C, Renou J, Collot V, Hervet M, Rault S, Gueiffier A . Reactivity of 3-iodoimidazo[1,2-a]pyridines using a Suzuki-type cross-coupling reaction. J Org Chem. 2000; 65(20):6572-5. DOI: 10.1021/jo000698z. View

5.

Hieke M, Rodl C, Wisniewska J, Buscato E, Stark H, Schubert-Zsilavecz M . SAR-study on a new class of imidazo[1,2-a]pyridine-based inhibitors of 5-lipoxygenase. Bioorg Med Chem Lett. 2012; 22(5):1969-75. DOI: 10.1016/j.bmcl.2012.01.038. View

6.

Kettle J, Brown S, Crafter C, Davies B, Dudley P, Fairley G . Diverse heterocyclic scaffolds as allosteric inhibitors of AKT. J Med Chem. 2012; 55(3):1261-73. DOI: 10.1021/jm201394e. View

7.

Snegaroff K, Nguyen T, Marquise N, Halauko Y, Harford P, Roisnel T . Deprotonative metalation of chloro- and bromopyridines using amido-based bimetallic species and regioselectivity-computed CH acidity relationships. Chemistry. 2011; 17(47):13284-97. DOI: 10.1002/chem.201101993. View

8.

Schroeder G, An Y, Cai Z, Chen X, Clark C, Cornelius L . Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily. J Med Chem. 2009; 52(5):1251-4. DOI: 10.1021/jm801586s. View

9.

Bode M, Gravestock D, Moleele S, van der Westhuyzen C, Pelly S, Steenkamp P . Imidazo[1,2-a]pyridin-3-amines as potential HIV-1 non-nucleoside reverse transcriptase inhibitors. Bioorg Med Chem. 2011; 19(14):4227-37. DOI: 10.1016/j.bmc.2011.05.062. View

10.

Blum C, Caldwell T, Zheng X, Bakthavatchalam R, Capitosti S, Brielmann H . Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists. J Med Chem. 2010; 53(8):3330-48. DOI: 10.1021/jm100051g. View

Regiocontrolled Microwave Assisted Bifunctionalization of 7,8-dihalogenated Imidazo[1,2-a]pyridines: a One Pot Double-coupling Approach