New approach to condensed pyrid-2-ones

We wish to report a simple procedure for the preparation of 5-substituted-thienopyridin-7-ones and 7-substituted-1,6-naphthyridin-5(6H)-ones, in good yields, from the dianions of 3-methylthiophene-2-carboxylic and 2-methylnicotinic acids on treatment with nitriles.


Introduction
Development of new approaches to the 2-pyridone ring is a topical area of continuous interest due to the high number of biologically active molecules containing this moiety 1 and to the facile conversion of pyridones to the corresponding pyridines. 2Tautomerism between 2-pyridones and 2-hydroxypyridines receives constant attention because these compounds may act as simple models for investigating the mechanisms of some enzymatic reactions or for discerning the behaviour of nucleic acids bases in connection with mutation due to base mispairing. 3Recent studies have shown the usefulness of 2-pyridones as intermolecular connectors between building blocks in material science. 4Thus, despite the large number of methods known for their synthesis, 5 new procedures are continuously being developed. 6eactions of aryl amide enolates with nitriles to afford 2-isoquinolines are known, 7 but our studies on the reactivity of dienediolates from unsaturated carboxylic acids had led us to a simpler synthesis of 4,6-disubstituted-and 3,4,6-trisubstituted-2-pyridones from easily accessible carboxylic acids and nitriles. 8On work-up, pure pyridone was isolated from the neutral fraction whereas the starting acid was recovered from the acidic fraction.The method has been readily reproduced showing it to be reliable. 9We found it interesting to study its extension to the synthesis of condensed heteroaromatic systems, both by introduction of heterocyclic nitriles and by using the well known o-toluic (2), 3-methyl-2-thiophenecarboxylic (3) and 2-methylnicotinic (4) acids that, after double deprotonation afford the corresponding lithium dianions.The synthetic interest of the dianion from o-toluic acid (2) has been amply demonstrated 10 but, surprisingly, the dianions from 3-methyl-2-thiophenecarboxylic (3) and 2-methylnicotinic (4) acids have received little study. 11

Results and Discussion
The results obtained on reaction of these dianions and nitriles (Scheme 1) are summarized in Table 1.
Although reaction conditions are not critical to obtain the corresponding pyridones, yields are variable and optimisation for each acid and nitrile was performed, specially those leading to 5substituted-thienopyridin-7(6H)-ones (7) and 7-substituted-1,6-naphthyridin-5(6H)-ones (8) as they render information about the generation and behaviour of 3-methyl-2-thiophenecarboxylic (3) and 2-methylnicotinic (4) dianions.Room temperature, 24 hours of reaction time and 1:1 ratio of acid and nitrile was always the best choice.On the other hand, the nature and amount of the amine used for acid deprotonation determines the reaction yield.In most cases, dienediolates of unsaturated carboxylic acids can be generated, without Barbier's reduction or Michael adduct formation, by deprotonation of the corresponding acid with butyllithium in the presence of a catalytic amount of amine. 12This renders dienediolates compatible with a large number of functional groups, as it happens with nitriles where self-condensation is minimized under these conditions.Unfortunately, this cannot be considered a general rule (see entries 6 to 9 in Table 1) and it is convenient to optimise the amine and its amount for each acid and nitrile, as used to happen in similar reactions.2-Pyridinecarbonitrile (e) is specially prone to give self-condensation under the basic conditions used, leading to complicated reaction mixtures until the right conditions, usually catalytic amount of amine, were found.In some cases (entry 12) only pure trimerization product, 2,4,6-tri(2-pyridyl)-1,3,5-triazine (9), could be obtained in a good yield (Figure 1).

Tautomerism
Both amidic and phenolic tautomeric forms of compound 6e precipitate from water in a 2:1 ratio.By treatment with chloroform, both tautomers can be easily isolated.The first is soluble in chloroform and the second is highly insoluble.Their spectroscopic data are consistent with the proposed structures for both tautomers and provide us with a model that allows us to establish the amide form as the major tautomer in the rest of the compounds described.

Conclusions
In conclusion it can be said that o-methylarenic acids may be converted, under suitable conditions, into the corresponding dianions which show similar nucleophilic behaviour to the dienediolates of unsaturated carboxylic acids.It has been shown that condensed heteroaromatic systems are obtained from these dianions and nitriles through a tandem addition-cyclization process.On work up, pure products are easily isolated from any remaining starting material.

Experimental Section
General Procedures.M.p.s. were determined with a Reichert apparatus and are uncorrected.IR spectral data were obtained as liquid films or KBr discs using a Perkin-Elmer 281 spectrophotometer.NMR spectra were recorded in CDCl 3 or deuterated DMSO solutions, using a Varian Unity 300 or Unity 400 spectrometer.A series of COSY, NOESY and HMQC nmr experiments were carried out to assign both 1 H and 13 C signals.Elemental analyses were determined by "Servicio de Semimicroanálisis del Centro de Investigación y Desarrollo (CSIC) de Barcelona".High resolution mass spectra were determined with a UG Autoespec spectrometer.Silica gel Merck 60 (230-400 mesh) was used for flash column chromatography, with hexane/diethyl ether mixtures for elution.All reactions were carried out under argon atmosphere, using standard conditions for exclusion of moisture, in oven dried glassware, in THF freshly distilled from blue benzophenone ketyl and with diethyl amine and diisopropylamine distilled from CaH 2 .The reaction temperature (-78 o C) was achieved by cooling with a CO 2 /acetone bath.Organic extracts were dried over anhyd MgSO 4 , and solutions were evaporated under reduced pressure with a rotary evaporator and a bath at 40 o C.

General procedure for the synthesis of 2-pyridones
Carboxylic acid (2.25 mmol) in THF (2 ml) was slowly added to a stirred mixture of nbutyllithium and dialkylamine (see Table 1) in THF (2 ml) at -78ºC, according to the method already described.The solution was stirred for 60 min at 0ºC and cooled again at -78ºC.Nitrile (2.25 mmol) in THF (2 ml) was added dropwise, and the solution stirred at room temperature for 24 hours.Water (20 ml) was added and the product isolated by crystallization from crude in most cases, leading to pure products.In other cases, water was added, extracted with dichloromethane (3x15ml) and the combined organic layers were washed with brine to neutral pH, and dried.Evaporation of the solvent gave crude 2-pyridone product.The aqueous layer was acidified under ice-cooling bath by careful addition of conc.hydrochloric acid and then extracted with ethyl acetate (3x 15 ml).The acidic organic layer was washed with brine, dried and evaporation of the solvent gave the recovered starting acid.

Table 1 .
Nucleophilic addition to nitriles