Synthesis of Poly-substituted 2-Pyridones via [3+2+1] Annulation Protocol from Baylis-Hillman Adducts

Abstract

The synthesis of a substituted 2-pyridone ring is an area of continuing interest due to its abundance in many biologically important compounds containing this moiety. Although numerous papers have been reported on the synthesis of this class of compounds, development of a new and efficient synthetic procedure is still required. Recently, we reported an efficient synthetic method for poly-substituted pyridines from the combination of BaylisHillman adducts (3 carbons), activated methylene compounds (2 carbons) and ammonium acetate (1 nitrogen) via [3+2+1] annulation protocol in good yields, regioselectively. In the previous paper, we used Baylis-Hillman adducts derived from methyl vinyl ketone and obtained 2methyl pyridine derivatives. In continuation of our research, we intended to prepare the valuable poly-substituted 2pyridones by using the Baylis-Hillman adducts of methyl acrylate 1a as shown in Scheme 1. The starting material 3a was synthesized from the reaction of Baylis-Hillman acetate 1a and methyl acetoacetate (2a) in 77% yield. The ester 3a indeed produced 2-pyridone 7a, albeit in low yield (16%), along with three other products, 4a (34%), 5a (7%) and 6a (5%), when subjected to the conditions previously employed for the synthesis of pyridine derivatives (NH4OAc (3.0 equiv)/AcOH/reflux). Increasing the reaction temperature or varying the solvent (propionic or butyric acid) did not improve the results. The use of NH4Cl or NH4OH was also not effective. Fortunately, during the examinations we found that the use of excess amounts of NH4OAc afforded good yield of 7a. The reaction gave much better yield of 7a (75%), while suppressing the formation of by-products 4a (4%), 5a (12%) and 6a (5%), when 3a was heated in AcOH with 20 equiv of NH4OAc. The use of excess amounts of NH4OAc might be beneficial for the isomerization of 4a to 7a, although the reason is not clear at this stage. Encouraged by the results we prepared starting materials 3b-g similarly from ethyl acetoacetate (2b), 2,4-pentanedione (2c), methanesulfonylacetone (2d), 1,3-cyclohexanedione (2e), deoxybenzoin (2f), and 1,3-indandione (2g) in 56-85% yields. The syntheses of 7b-g were carried out by the same method for 7a and the results are summarized in Table 1. Various 2-pyridone derivatives 7b-g were synthesized in 64-82% yields including bicyclic (entry 5) and tricyclic compound (entry 7). In all cases trace amounts of the corresponding benzylidene compounds, alcohols, and benzoyl derivatives were observed on TLC, but we didn’t isolate them except entry 1 (vide supra, Scheme 1). The formation of alcohol 5a and benzoyl derivative 6a could be explained