Synthesis of Aza Coumarines by Nucleophilic Addition of Acetylenic Esters Catalysed by Ph 3 P

3-Hydroxypyridine undergoes a smooth reaction with dialkyl acetylenedicarboxylates in the presence of triphenylphosphine to produce alkyl 2-oxo-2H-pyrano[3,2-b]pyridine-4-carboxylate and dialkyl -2-[4(alkoxycarbonyl)-2-oxo-2-H-pyrano[3,2-b]pyridin-6-yl]-2-butenedioate in high yields. (doi: 10.5562/cca1725)


INTRODUCTION
Coumarins are of interest because they constitute an important class of naturally occurring compounds, many of which exhibit useful and diverse biological activity. 1 In addition, other coumarins are of much interest a result of their toxicity, 2 carcinogenicity, 3 and photodynamic effects. 4In particular, those coumarins fused to pyridines have been reported to possess antiallergic, 5 antidiabetic, 6 and analgesic properties. 7Also, a considerable number of natural or synthetic derivatives of coumarin have found pharmaceutical applications. 8,9hus, the synthesis of this heterocyclic nucleus is of current interest.1][12][13][14] We have recently described a new and operationally convenient approach to the synthesis of carboxymethyl coumarines based on aromatic electrophilic substitution reaction between the conjugate base of substituted phenols, catechol, resorcinol, hydroquinone, and pyrogallol. 15,16In continuation of our current interest in the development of new routes to heterocyclic and carbocyclic systems, [17][18][19] we report here a simple one-pot synthesis of functionalized 5-Aza coumarines 3, 4. Thus, reaction of 3-hydroxypyridine 1 with dialkyl acetylenedicarboxylate 2 in the presence of triphenylphosphine leads to the corresponding coumarins 3, 4 (Scheme 1).

RESULT AND DISCUSSION
The reaction of 2-hydroxy pyridine (1) with dialkyl acetylenedicarboxylate (2) in the presence of Ph 3 P proceeded spontaneously in toluene at reflux temperature and needed within 24 h to finish.On the other conditions (changing solvents, variations of molar ratios) The 1 H NMR spectrum of 4a exhibited three single sharp line for the methoxy group at δ = 3.84, 3.99 and 4.05 ppm, together with two singlet at δ = 6.88 and 6.89 ppm for methine protons.The 13 C NMR spectrum of 4a exhibited fifteen sharp lines in agreement with the proposed structure.Partial assignment of these resonances is given in the experimental.Mechanistically, 15,16 it is conceivable that the reaction involves the initial formation of a zwitterionic intermediate between Ph 3 P and the acetylenic compound and subsequent protonation of reactive 1:1 adduct followed by electrophilic attack of vinyltriphenylphosphonium cation on the aromatic ring at the ortho position relative to the strong activation group.The product is presumably produced by intramolecular lactonization of the unsaturated diester 5 (Scheme 2).
Reaction leading to 4, involves formation of the zwitterionic intermediate which is protonated by 3hydroxypyridine.Then it is attacked by the conjugate base to produce ylide, in next step the intermediate undergoes proton transfer to furnish the 1,3-diionic structure.At the end, it is converted to the final product by loss of Ph 3 P.

CONCLUSION
In conclusion, we have described a convenient route to aza coumarines, through nucleophilic addition to dialkyl acetylenedicarboxylate.These functionalised coumarines may be considered as potentially useful synthetic intermediates because they possess atoms with different oxidation states.The present method has the advantages that not only are the reaction performed under neutral conditions, but also the substances can be mixed without any modification.The simplicity of the present procedure makes it an interesting alternative to other approaches.

General Procedure for the Preparation of compound 3
To a stirred solution of 0.52 g of Ph 3 P (2 mmol) and 0.19 g 1 (2 mmol) in toluene (10 ml) was added drop wise a mixture of 2 (2 mmol) in toluene (2 ml) at room temperature over 5 min.The reaction mixture was heated under reflux for 24 h.The solvent was removed under reduced pressure, and the viscous residue was purified by column chromatography (SiO2; hexane/AcOEt 4:1) to afford the pure adducts.