Abstract
A straightforward synthesis of cyclopenta(b)pyridin-2,5-dione is reported starting from the commercially available 2-bromo-6-methoxypyridine. The overall route consists in a first sequence of regioselective ortho lithiation and methoxycarbonylation followed by Heck vinylation, alkene reduction, cyclization and decarboxylation.
Highlights
A recent pharmacological evaluation of various functionalized 2-pyridones as cardiotonic agents has revealed that the cyclopenta[b]pyridin-2,5-dione (1) displays a high activity rather similar to Milrinone (2) which is the most effective non glycosidic cardiotonic agent clinically used for the treatment of severe heart failure.[1]
We recently described a novel synthesis of 6-methyl cyclopenta[b]pyridin-5-one (8) based on Heck vinylation of 2-bromo-6-methyl nicotinate (6) with methacrylate affording the pyridylacrylate intermediate 7, alkene reduction and Dieckmann condensation as depicted in Scheme 1.4 We wish to report here our results on the application of the latter method to the preparation of the cyclopenta[b]pyridin-2,5-dione (1)
The pyridylacrylate 9 could be first prepared by Heck vinylation of bromopyridine 10
Summary
A recent pharmacological evaluation of various functionalized 2-pyridones as cardiotonic agents has revealed that the cyclopenta[b]pyridin-2,5-dione (1) displays a high activity rather similar to Milrinone (2) which is the most effective non glycosidic cardiotonic agent clinically used for the treatment of severe heart failure.[1]. Reagents and conditions: (i) methyl acrylate (2.5 equiv.), Pd2[allyl2Cl2] , P(o-Tol)[3], NaOAc (3 equiv.), toluene: DMA (3:1), 92%; (ii) H2 (1 atm), Pd/C (10 mol %), MeOH, r.t., 2h, 93%; (iii) NaOMe, THF, reflux, 2h, 75%; (iv) HCl (5 M), reflux, 3h, 84%.
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