Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

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Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

Green Chem., 2016, Advance Article
DOI: 10.1039/C6GC01601D, Communication

Open Access

  This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Michael R. Chapman, Maria H. T. Kwan, Georgina E. King, Benjamin A. Kyffin, A. John Blacker, Charlotte E. Willans, Bao N. Nguyen
A route to access the privileged imidazo[1,2-a]pyridine scaffold in one step, 1-10 minutes using only aqueous NaOH, is reported.

Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

Michael R. Chapman,^a   Maria H. T. Kwan,^a   Georgina E. King,^a  Benjamin A. Kyffin,^a   A. John Blacker,^a  Charlotte E. Willans*^a and   Bao N. Nguyen*^a  

*Corresponding authors

^aInstitute of Process Research and Development, School of Chemistry, University of Leeds, Leeds, UK
E-mail: b.nguyen@leeds.ac.uk

Green Chem., 2016, Advance Article

DOI: 10.1039/C6GC01601D

see………..http://pubs.rsc.org/en/Content/ArticleLanding/2016/GC/C6GC01601D?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

see http://pubs.rsc.org/en/content/articlehtml/2016/gc/c6gc01601d

A novel, rapid and efficient route to imidazo[1,2-a]pyridines under ambient, aqueous and metal-free conditions is reported. The NaOH-promoted cycloisomerisations of N-propargylpyridiniums give quantitative yield in a few minutes (10 g scale). A comparison of common green metrics to current routes showed clear improvements, with at least a one order of magnitude increase in space-time-yield.

Scheme 1 Synthetic methods to assemble imidazo[1,2-a]pyridines.

 

Fig. 1 A scaled up reaction setup. (a) before reaction; (b) during addition of 1a (zoomed in); (c) phase separation at the end of the reaction (zoomed in).

2-Aminopyridine (6.12 g, 65.0 mmol), propargyl bromide (11.6 g of an 80 wt.% solution in toluene, 78 mmol, 1.2 equiv) and 2-propanol (200 mL) charged to a round bottomed flask and stirred at 50 C for 2 hours. After which, a pale yellow solid precipitated from solution. This was filtered and washed with diethyl ether (2 x 30 mL) followed by drying in vacuo to give product 1a in 11.1 g (52 mmol, 80% isolated yield). To a stirring solution of NaOH (1.90 g, 47.5 mmol) in deionised H2O (70 mL) was added 2-amino-1- (2-propynyl)pyridinium bromide 1a (10.0 g, 47.0 mmol) via powder addition funnel (a) over a period of 5 minutes. Immediately upon addition, the solution phase turned yellow (b – d) and a yellow oil became dispersed as a distinct separate phase (e). The oil (product) was subsequently extracted into EtOAc (2 × 30 mL) (f), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford imidazo[1,2-a]pyridine 2a as a spectroscopically pure pale yellow oil. Yield: 6.12 g, 98% yield.

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