A convenient synthesis of cyclopenta[b]pyridin-2,5-dione as a non-glycosidic cardiotonic agent

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


Introduction
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 Cyclopenta[b]pyridin-2,5-dione (1) constitutes also an interesting tensor of pharmaceutics exemplified by the antibacterial product 5 and a buildingblock for the access to 2-cyclopenta[b]pyridin-5-one (3) as seco analogues of 8-azasteroids (4). 2

Results and Discussion
Despite the fact that the cyclopenta[b]pyridin-2,5-dione (1) is gaining interest as biologically active compounds and valuable building-blocks only two methods of preparation could be found in the literature.The first synthesis of cyclopenta[b]pyridin-2,5-dione (1) was first reported in 1954 (6 steps synthesis and a 13 % overall yield). 3Mosti and his team published in 2003 a novel synthetic route based upon a one-pot and two-step construction of the 2-pyridone ring from the cyclopenta-1,3-dione. 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).Our retrosynthetic analysis suggests that 2-bromo-6-methoxynicotinate (10) could be a valuable precursor for this purpose (scheme 1).The pyridylacrylate 9 could be first prepared by Heck vinylation of bromopyridine 10.The expected cyclopenta[b]pyridin-2,5-dione (1) would be then obtained by reduction of the alkene followed by a cyclization-decarboxylation sequence.The success of this novel approach mainly depends on the access to the unknown 2-bromo-6-methoxynicotinate 10.Two possible routes could be designed: (i) the regioselective displacement of a bromine atom at position 2 of the methyl 2,6-dibromonicotinate (11) which could be readily prepared in two steps from the 2,6-dichloronicotinic acid by bromination and esterification 7 or (ii), the regioselective methoxycarbonylation of the commercially available 2-bromo-6-methoxypyridine (12).We first attempted to displace the bromine atom at position 2 of ethyl 2,6-dibromonicotinate (11) with sodium methoxide.Treatment of 11 with 1.5 equivalent of sodium methoxide was carried out in refluxing MeOH for 24h following the Hirokawa's protocol. 5A complete conversion of the starting material was observed and a mixture of 2-and 6-monosubstituted products 10 and 14 in a 7:3 ratio ( 1 H NMR) could be obtained in 75 % yield.Unfortunately, the two regioisomers 10 and 14 could not be separated by chromatography.Moreover, replacement of sodium methoxide by potassium methoxide also led to a 1:1 mixture regioisomers 10 and 14.We then shifted to the second route based on the regioselective methoxycarbonylation at position 3 of 2-bromo-6-methoxy pyridine (12).To this purpose, we first examined the lithiation of 2-bromo-6-methoxy pyridine (12) by treatment with hard bases such as lithium amides in THF before quenching the lithio intermediates with D 2 O (Table 1).A first set of lithiation experiments was achieved using 2,2',6,6'-tetramethylpiperidinyl-lithium (LTMP) at -78 °C (entries 1-3).a The ratio was determined by 1 H NMR spectroscopy No deuterated product was obtained using 1 equivalent of LTMP whereas the 5-deuterated compound 15b was selectively formed in 64% yield using 2 equivalents of LTMP.The starting material conversion could be significantly improved employing 3 equivalents of LTMP leading to a mixture of 3-and 5-deuterated products (15a, 15b) in 2:8 ratio in favor of the 15b isomer.The less hard lithium diisopropylamine (LDA) was also checked (entries 4-7).Treatment of 12 with 2 equivalents of LDA followed by D 2 O trapping specifically provided the 3-deuterated product 15a in 15 % yield (entry 4).This result could be related to the higher acidity of the proton at position 3. Surprisingly, we observed that the yield of 3-deuterated compound 15a was not improved using 3 equivalents of LDA at the same temperature (entry 5).Moreover warming the 3-lithio anion from -78°C to -50 °C6 before trapping with D 2 O afforded a mixture of 15a and 15b (entries 6,7).The 3-lithio anion formed by treatment of 12 with 2 equivalents of LDA at -78°C in THF (table 1-entry 4) did not react with methyl cyanoformate but could be trapped by carbon dioxide to give the 3-bromo-6-methoxynicotinic acid (16) after acidic treatment.Acid (16) was isolated in 13 % yield but the unreacted starting material 12 could be was readily recovered and re-used.Finally 16 was obtained in 41 % overall yield after five lithiation-carboxylation sequences.Esterification of 16 gave the expected methyl 2-bromo-6-methoxy nicotinate (10) in 92 % yield.
Heck vinylation of 10 with methyl acrylate using the η 3 -allylpalladium chloride dimer with P(o-Tol) 3 complex as catalyst in toluene and dimethylacetamide (DMA) as co-solvent 4 provided the β-2-pyridyl acrylate 9 in an excellent 82% yield.The use of DMA is a crucial parameter as the vinylation of 10 failed without this co-solvent.Reduction of the alkene under soft conditions provided diester 17 which could be cyclized by a Dieckmann condensation with sodium methoxide to methyl cyclopenta[b]pyridine-5-one-6-carboxylate (18) in 70% overall yield.Finally, treatment with hydrochloric acid allows hydrolysis, decarboxylation and demethylation of 18 to give cyclopenta[c]pyridine-2,5-dione (1) in 84 % yield.

Conclusions
A convenient route to cyclopenta[b]pyridin-2,5-dione (1) is reported starting from methyl 2bromo-6-methoxynicotinate (10) through a 4 steps synthesis, vinylation, alkene reduction and cyclization-decarboxylation, in 48% overall yield.Two routes were studied for the previous preparation of the parent methyl 2-bromo-6-methoxynicotinate (10).Regioselective displacement of the bromine atom of methyl 2,6-dibromonicotinate (11) by the sodium or potassium methoxide could not be applied leading to a mixture of regioisomers which could not be separated by chromatography.The second approach was based upon the regioselective carboxylation of the commercially available 2-bromo-6-methoxypyridine (12) at position 3 of the pyridine nucleus.The regioselective lithiation-carboxylation and esterification of 12 at position 3 was achieved using LDA at -78°C in THF to give the expected methyl 2-bromo-6methoxynicotinate (10) in 12 % yield in two steps.

Experimental Section
General Procedures.Tetrahydrofuran (THF), ether (Et 2 O) were pre-dried with pellets of KOH and distilled over sodium benzophenone ketyl under Ar before use.CH 2 Cl 2 , NEt 3 and toluene were distilled from CaH 2 .Methanol and ethanol were distilled from magnesium turnings; dimethylacetamide was distilled over 4 A molecular sieves.For Flash chromatography, Merck silica gel (70-230 mesh) was used.The melting points were measured on a Kofler melting points apparatus and were not corrected.The 1 H NMR and 13 C NMR spectra were recorded with a Bruker Avance-300 spectrometer operating at 300 MHz.Commercially available starting materials were used without further purification.Infrared spectra were recorded on a Perkin-Elmer FT-IR 1650 spectrophotometer.Elemental analysis of compounds was carried out on a Carlo Erba 1160.Mass spectra were recorded on a JEOL JMS AX-500 spectrometer, in electronic impact (EI).The starting compound 12 is commercially available.

Preparation of 6-methoxy-2-bromonicotinate (10) Methyl 2,6-dibromonicotinate (11).
To a stirred solution of 2,6-dibromonicotinic acid 7 (500 mg, 1.8 mmol) and 3 drops of DMF in dry CH 2 Cl 2 (10 ml) was slowly added oxalyl chloride (172 µL, 2.0 mmol) at 0°C.The mixture was stirred at room temperature for 1h and solvents were removed in vacuo.To the crude product was added dry methanol (10 ml) at 0 °C and the resulting solution was stirred for 2 h at room temperature.Methanol was removed in vacuo and the crude solid was dissolved in CH 2 Cl 2 (10 ml).The pH of the aqueous layer was then adjusted to 7 by adding aq.K 2 CO 3 (2M).The separated organic layer was washed three times with water, dried (MgSO Procedure for nucleophilic substitution using sodium methoxide.To a stirred solution of methyl 2,6-dibromonicotinate (11, 1.5 g, 5.0 mmol) in dry MeOH (20 ml) was added NaOMe (270 mg, 5.0 mmol).The mixture was refluxed for 24 h and then poured into cold aq.NaHCO 3 (5 %, 50 ml) and the product was extracted with ether (3х20 mL).The separated organic phase was separated and concentrated in vacuo.Ether (40 mL) was added to the crude liquid and the organic phase was washed with brine (40 mL), dried (MgSO 4 ) and concentrated in vacuo.The crude product was purified by chromatography on silica gel (CH 2 Cl 2 ) to give a (7:3) mixture of 10 and 14 (923 mg, 75 %).