2-Amino-4H,5H-pyrano[4,3-b]pyran-5-ones and

Pharmaceutical Institute, Christian-Albrechts University of Kiel, Gutenbergstr. 76, D-24118 Kiel,GermanyTel.: (+49-431) 880-1118, Fax: (+49-431) 880-1352, E-mail: dheber@pharmazie.uni-kiel.de*Author to whom correspondence should be addressed.Received: 7 December 1999 / Accepted: 31 December 1999 / Published: 21 January 2000Abstract: Reaction of 4-hydroxy-6-methyl-2-pyrone (1a) as well as 4-hydroxy-6-methyl-2(1H)-pyridones (1b-d) with arylmethylene malononitriles or arylmethylene methyl cyano-acetates (2a-h) leads to the formation of the very stable 5,6-fused bicyclic 2-amino-4H-pyran derivatives 3a-3af.Keywords: pyrano[4,3-b]pyran, pyrano[3,2-c]pyridine, arylmethylene malononitrile, aryl-methylene cyanoacetate, Michael addition.IntroductionWiener et al. first published [1] that 4-hydroxycoumarin cyclized through Michael addition to ben-zylidene malononitrile in pyridine as solvent to give a derivative of 2-aminopyrano[3,2-c]benzopyran(A) (Figure 1). Later, Junek and Aigner [2] found a second case of this heterocyclization via additionof 4-hydroxy-6-methyl-2-pyrone (1a, “triacetic acid lactone”, Scheme 1) to tetracyanoethylene, thuspreparing a substituted 2-amino-4H,5H-pyrano[4,3-b]pyran (B). Many years thereafter, Shaker [3] re-

Meanwhile, two further communications on the same subject appeared in the literature.Mekheimer et al. [6] reported the cyclization of 4-hydroxy-6-methyl-2(1H)-pyridone (1b) with arylmethylene malononitriles and arylmethylene cyanoacetic esters to the corresponding pyrano [3,2-c]pyridines (3f and their analogues, Scheme 1), thus independently covering a small part of our results.Also Piao and Imafuku [7] published a preliminary paper dealing with the preparation in a similar way of some novel 4H,5H-pyrano [4,3-b]pyran-5-ones of type B from triacetic acid lactone without, however, giving spectral and analytical characterization of their products.
We now wish to report the general procedure for the preparation of both compound classes and to fully characterize the numerous new substances synthesized by us.

Results and Discussion
The starting compounds 1a-d react with the Knoevenagel products 2a-h [8] in an equimolar ratio by refluxing in methanol for 1-6 h in the presence of small amounts of piperidine.Both reaction steps, the Michael addition of C-3 of 1 to the β-position of 2 and the nucleophilic intramolecular addition of the 4-hydroxy group to the cyano group, occur as one-pot process.The products 3a-3af (Table 1) usually crystallize on cooling and can be easily isolated to give yields in the range from 56 to 95%.Beside 4hydroxy-6-methyl-2(1H)-pyridone (1b), its N-substituted derivatives 1c,d were also successfully employed in the reaction.
In contrast with the reported statement that the ethyl α-cyanoacrylic esters react only in refluxing pyridine as solvent [6], we found that the methyl esters 2a,c,e,g (Y = COOCH 3 ) did give good to excellent yields of the corresponding products 3 by using the same general procedure as for the malononitriles (reflux in methanol, piperidine).
The structure of the products 3 could be unambiguously deduced from their spectral properties.The primary amino group showed two IR absorption bands at 3357-3500 and 3133-3330 cm -1 and a sharp 2H-singlet at δ = 6.92-7.83ppm in their 1 H-NMR spectra (cf.[6]).In the IR spectra, all 3-carbonitriles absorbed at 2181-2217 cm -1 (CN) whereas the methyl 3-carboxylates gave bands in the range 1657-1696 cm -1 for ester carbonyl group.The mass spectra of 3 confirmed the corresponding molecular masses.
The stability of the compounds 3 with respect to opening of the 2-aminopyran ring was examined on the product 3f as a model compound (no ester function, stable lactam ring).Surprisingly, it turned out that 3f is rather stable under hydrolytic conditions (diluted or concentrated sulphuric and hydrochloric acid, mixture of acetic and hydrochloric acid, ethanolic potassium hydroxide).Our trials to perform some chemical transformations of 3f, similar to those described in the literature [3,6], also failed.

General
Melting points were determined in open capillary tubes with a Büchi 535 melting point apparatus (Switzerland).IR spectra (nujol) were recorded on a Shimadzu FTIR 8101M spectrometer (Japan), ν in cm -1 .Mass spectra were measured on a Varian MAT 711 spectrometer (Germany) at 70 eV (direct inlet). 1 H NMR were recorded on a Bruker DRX-250 spectrometer at 250 MHz (Germany), δ (ppm) referenced to TMS (internal).Microanalyses were carried out in the Microanalytical Laboratory of the Institute of Organic Chemistry and Isotope Research, University of Stuttgart, Germany.TLCmonitoring: pre-coated aluminium sheets Merck, 0.2 mm layer of silica gel F 254 , eluted by hexane/acetone/methanol (5:3:2, vol.parts), detection by Camag UV-lamp (254/366 nm).Yields of isolated, TLC-homogeneous products are given.

General procedure for preparation of compounds 3a-3af
Into a stirred mixture of 4-hydroxy-6-methyl-2-pyrone (1a; 126 mg, 1.0 mmol) or of the corresponding 4-hydroxy-2(1H)-pyridone (1b-d; 1.0 mmol) and the α,β-unsaturated nitrile (2a-h, 1.0 mmol) in methanol (5.0 ml), 1-2 drops of piperidine were added and the mixture was refluxed under stirring for a period of time given below for each product.After cooling to 20-25°C, the separated crystals were filtered, washed with cold methanol and air-dried to give the corresponding product 3a-3af.The product's purity was controlled by TLC.When necessary the crude product was recrystallized from the corresponding solvent given below.