A Preparative Route to Fused 4-Hydroxy-3-phenylindeno(benzothieno)pyridin-2-ones (2002)

Syntheses of fused 4-hydroxy-3-phenylindeno(benzothieno)pyridin-2one derivatives (1a,b) are described.From extensive reseach over the last twenty years, it has been concluded that L-glutamate is the major fast excitatory neurotransmitter in the mammalian central nervous system (CNS). 1 Glutamate plays an essential role in many physiological CNS functions through the activation of three major types of postsynaptic ionotropic receptors designated according to the non-natural substances that selectively activate them: NMDA (N-methyl-D-aspartate), AMPA (2-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid) and kainate receptors. 2In addition, glutamate activates several types of metabotropic receptors signaling through a G-protein coupled. 3Competitive or non-competitive antagonists of these biological targets (such as AMPA receptor) acting at the N-methyl-D-aspartate (NMDA) receptor subtype have been proposed as potential neuroprotective agents in human. 4In connection with our own research projects directed towards the synthesis of such potent AMPA receptor antagonists, 5 an easy and efficient method leading to fused 4-hydroxy-3-phenylbenzothienopyridin-2-one (1a) and 4-hydroxy-3phenylindenopyridin-2-one (1b) has been developed (Figure 1).To our knowledge, only 4-hydroxy-3-phenylpyridin-2-one (2), 6 4-hydroxy-3-phenyl-5,6,7,8-tetrahydroquinolin(1,8-naphthyridine)-2-one (3a,b), 7 4-hydroxy-3-phenylquinolin-2-one (4), 8 4-hydroxy-3-phenyl-1,8(1,5)-naphthyridin-2-one (5a,b), 9 5-hydroxy-6-phenylpyrido[2,3-d]pyrimidin-7-one (5c), 10 pyridino-[2,3-d]pyrimidinone (6) 11 and 4-hydroxy-5-phenylthieno[2,3-b]pyridin-6-one derivatives (7) 11 were described (Figure 1).We therein report the efficient synthesis of new fused pyridin-2-one derivatives (1a) and (1b) 13 bearing original fused moieties, within a three steps synthesis as summarized in Schemes 1 and 3.As illustrated in Scheme 1, condensation of 2-cyanothiophenol (8) with ethyl bromoacetate in the presence of 5% aq.NaOH afforded the ethyl acetate derivative (9) with 53% yield.Action of an excess of NaH (2 eq.) with 9 in THF at reflux did not lead to the expected cyclic compound (10) but to the 3aminobenzo[b]thiophene (11) with 40% yield.This synthetic pathway represents an convenient procedure for the preparation of 11. 14 Changing our mind, and according to the procedure described by K. Clarke and his co-workers, ethyl 3-amino[1]benzothiophene-2-carboxylate (10) 15 was easily prepared in a one-step synthesis from 8 by the action of potassium carbonate with ethyl bromoacetate in acetone at reflux with a high yield (81.5%).Then, treatment of 10 with phenylacetyl chloride in the presence of triethylamine at reflux gave 12 with 78.5% yield.Finally, the intramolecular ring closure reaction of the benzothiophene derivative (12) was carried out using 3 equivalents of 1M lithium bis(trimethylsilyl)amide (room temperature to reflux) in THF affording the pure 4-hydroxy-3-phenylbenzothienopyridin-2-one (1a) with 51% yield.Our initial strategy to synthesize 4-hydroxy-3-phenylindenopyridin-2-one (1b) was to use the indene derivative (15) and apply the same synthetic methodology as that for the preparation of 1a.However, the