Synthesis of New Potentially Bioactive Bicyclic 2-Pyridones

Three convenient methods of reduction of the nitro group of 5-nitroimidazoles and 5-nitrothiazole that bear a diethylmethylene malonate group in an ortho-like position with respect to the nitro group and cyclization of the resulting amino derivatives are reported. These reactions afforded the target bicyclic 2-pyridones in good to excellent yields.


Introduction
As part of a program directed towards the synthesis of new bicyclic 2-pyridones of pharmaceutical interest bearing an ester group in the 6 position, we have reported a rapid alternative syntheses to the Knoevenagel reaction, and prepared nitroheterocycles containing a diethylmethylene malonate group in an ortho-like position with respect to the nitro group [1]. This paper describes the synthesis of bicyclic 2-pyridones in a two step procedure: reduction of the nitro group in 5-nitrothiazole and 5nitro-imidazole rings bearing the diethylmethylene malonate group followed by cyclization.

Results and Discussion
Due to the high functionalization of the precursors of the pyridones (malonic acid diethyl ester, conjugated double bond, nitro group, heterocyclic ring with a nucleophilic heteroatom), we had to study the reduction reaction in order to selectively reduce the nitro group. Moreover, we studied the reactivity of the amino group obtained from the nitro group reduction and determined if the cyclization reaction could be made in a one-pot reduction-cyclization.
In our preliminary study we focused on imidazoles and our first choice to reduce the nitro group of (1)  Unfortunately, this method was found to not be applicable to all nitroimidazoles. The 5-nitroimidazoles without alkyl substituents in the 2-position gave poor yields, so we had to find more general conditions and switched to other metal halides. We thus found that SnCl 2 in ethanol gave the best results. Reduction of compound 3 occurred with five equivalents of SnCl 2 in ethanol at 70 °C, then the corresponding amine was treated with two equivalents of magnesium (powder) in methanol at room temperature during 20 h leading to the corresponding bicyclic pyridone 4 in 92% yield (Scheme 2). 2) Mg (2 equiv.) MeOH

Scheme 2.
The imidazopyridone 4 was obtained as the methyl ester due to the transesterification reaction in methanol. These conditions were applied to the N-ethyl imidazole analogue of 3, but gave the imidazopyridone 6 in poor yield. No transesterification was observed in this case (Scheme 3).
In order to obtain the imidazopyridone 7 containing a carboxylic acid ethyl ester moiety in the 6position, transesterification conditions with sodium ethoxide in ethanol (room temperature, 24 h) were used from compound 4, leading to the desired bicycle 7 in excellent yield (92%) (Scheme 4).

Scheme 4.
On the other hand, both the procedures previously described in this paper gave very poor yields of thiazolopyridone 9 when applied to the nitrothiazole 8. Consequently, we tried other reaction conditions using iron in glacial acetic acid as reported in our previous publication [7]. Under these conditions diethyl 2-[(2-methyl-5-nitrothiazol-4-yl)methylene]malonate (8) afforded the target lactam 9 in 90% yield (Scheme 5).

Conclusions
We have presented three convenient procedures for the synthesis of new bicyclic 2-pyridones from methylene malonic acid ethyl ester derivatives. Further studies are now in progress to determine the general character of these methods allowing reduction and cyclization of highly functionalized nitroheterocyclic compounds.

Acknowledgements
Financial support from Sanofi-Synthélabo Recherche and CNRS are highly appreciated. We are also grateful to Dr Mustapha Kaafarani and Dr Armand Gellis for fruitful discussions.

a) Reduction using Titanium(III) chloride
In a two-necked flask equipped with a reflux condenser, titanium(III) chloride (30 wt% solution in 2N hydrochloric acid, 21 mL) were added dropwise on a solution of 1 (1.25 g, 4.02 mmol) in water (42 mL) and acetone (82 mL). The mixture was stirred at room temperature for 20 h. Then, a saturated aqueous solution of Na 2 CO 3 was added. The green cake obtained was filtered and washed with dichloromethane, then, the solvent was dried over MgSO 4 and removed under reduced pressure. The resulting amine was used for the cyclization reaction without any further purification.

b) Cyclization using sodium ethoxide in ethanol
In a two-necked flask equipped with a reflux condenser, ethanol (5 mL) and sodium (100 mg) were stirred until complete dissolution. A solution of the previously obtained amine in ethanol (45 mL) was added rapidly. This mixture was stirred at room temperature for 14 h and then at the reflux temperature of the ethanol for 2 additional hours. After cooling, water was added to the mixture, the solution was then extracted with chloroform. The combined organic layers were dried over MgSO 4

Preparation of ethyl 2-methyl-5-oxo-4,5-dihydrothiazolo
In a two-necked flask equipped with a reflux condenser, 8 (100 mg, 0.314 mmol) and glacial acetic acid (5 mL) were stirred and heated at reflux. To this solution was added iron powder (250 mg, 4.46 mmol) and the stirred mixture was heated at reflux for 2 h. After cooling, the solution was filtered through Celite and washed with glacial acetic acid. The acetic acid solution was evaporated on a rotary evaporator and the residue made basic with aqueous Na 2 CO 3 . The aqueous layer was extracted with chloroform. The combined organic layer was dried over MgSO 4 and evaporated to give 70 mg of 9 (90% yield). An analytical sample of 9 was obtained as a beige solid, mp 114.6 °C, by crystallization (isopropanol); 1