Enamino esters in the synthesis of heterocyclic systems. Transformation of diethyl acetone-1,3-dicarboxylate into poly-substituted 1,2,7,8-tetrahydro-2,7-naphthyridine-4-carboxylates

A simple three step synthesis of aminosubstituted 1,2,7,8-tetrahydro-2,7-naphthyridine-4-carboxylates is described. Ethyl (3-cyano-6-ethoxy-2-oxo-1,2-dihydropyridin-4-yl)acetate 3 , formed by the condensation of diethyl acetone-1,3-dicarboxylate with malononitrile, was transformed with N , N-dimethylformamide dimethylacetal (DMFDMA) into ( E )-ethyl 2-(3-cyano-6-ethoxy-2-oxo-1,2-dihydropyridin-4-yl)-3-(dimethylamino)propenoate


Scheme 1
In connection with our interest in the synthesis of various heterocyclic systems 2,3 and natural products 4 compound 4, as a polyfunctional enamino ester, seems to be an excellent starting compound for the synthesis of 2,7-naphthyridine derivatives.The first preparation of 2,7naphthyridines has been been reported in 1958. 5There are several reviews dealing with the synthesis and application of 2,7-naphthyridines. 6Only few synthetic methods have a wide scope and generality.The cyclization of o-cyano-pyridineacetonitriles or -acetaldehyde equivalent derivatives, 7,8 and a general synthesis of naphthyridines and their N-oxides starting from bromopyridines followed by electrophilic substitution with DMF, conventional palladiumcatalyzed cross-coupling with acetylenes, and reaction with ammonia have been published, recently. 9,10In this communication we extend the application of enamino esters to the synthesis of 1,2,7,8-tetrahydro-2,7-naphthyridine-4-carboxylates.

Results and Discussion
In the reaction of (E)-ethyl 2-(3-cyano-6-ethoxy-2-oxo-1,2-dihydropyridin-4-yl)-3-(dimethylamino)propenoate 4 with a mixture of aqueous ammonia and ethanol under reflux the dimethylamino group was substituted with an amino group to give intermediate 5, which, without isolation cyclized into the 1-aminonaphthyridine derivative 6b.Similarly, heating of 4 in a mixture of aqueous solution of hydrochloric acid in methanol substitution of dimethylamino group by hydroxy group took place to form the intermediate 7, which was, without isolation, cyclized into 1H-pyrano [3,4-c]pyridine-4-carboxylate 8.In the reaction with aniline only substitution of the dimethylamino group occurred to give the corresponding acrylate derivative, as a 1:1 mixture of (E)-9a and (Z)-9b isomers, which did not cyclize by further heating.In the reaction of 4 with aryl-and heteroarylhydrazines 10a-i in methanol in the presence of catalytic amounts of hydrochloric acid substitution of the dimethylamino group took place to give intermediates 11, which were, without isolation, further cyclized under reaction conditions.Two types of products could be formed.Cyclization could occur involving either the ester group to form pyrazolidinone derivatives 12, or involving the cyano group forming naphthyridine derivatives 13, respectively.Since the ester group is present in the final product as shown by IR and 1 H NMR spectra, while the cyano group is absent in IR spectra, one can conclude that 2,7naphthyridine derivatives 13 were formed.In these reactions always trace amounts of 1-amino derivative 6b and pyrano [3,4-c]pyridine derivative 8 are formed as side products.In the reaction of 4 with benzylhydrazine in the presence of aqueous hydrochloric acid in methanol only a mixture of benzylidenehydrazinylacrylate 14 and 8 was formed (Scheme 2).

Scheme 2
The structures were confirmed by 1 H NMR and IR spectra, MS and elemental analyses for C, H, and N. 1 H NMR spectra of compounds 13a-i exhibit besides typical signals for ethoxy group at position 6, ethyl ester group at position 4 and protons of aromatic or heteroaromatic groups attached at position 2, a singlet at δ = 7.90 -8.19 ppm for H3 and a singlet at δ = 6.69 -7.14 ppm for H5.For compound 6 the structure was confirmed also by X-ray analysis showing that this compound exists in the 1-amino form 6b and not in 1-imino tautomeric form 6a (Figure 1).

General procedure for the synthesis of compounds (13a-i)
A mixture of compound 4 (157 mg, 0.51 mmol) and aryl-or heteroarylhydrazine 10a-i (0.54 mmol) dissolved in MeOH (1.5 to 4 mL) and hydrochloric acid (37%, 0.3 mL) was heated under reflux for 1.5 to 4 h.The yellow precipitate was, after cooling, collected by filtration and washed with MeOH to give analytically pure 13a-i.The following compounds were prepared accordingly: Ethyl 6-ethoxy-1-imino-8-oxo-2-(phenylamino)-1,2,7,8-tetrahydro-2,7-naphthyridine-4-carboxylate (13a).This compound was prepared from 4 and phenylhydrazine hydrochloride 10 in MeOH (1.3 mL), reflux 2.5 h.Yield: 96 mg (51%), yellow microcrystals, m.p. 241-243 °C. 1 12 were used for indexing and scaling of the data and the structures were solved by means of SIR97. 13Refinement was done using Xtal3.6 14 program package and the crystallographic drawing was prepared by ORTEP-3. 15Crystal structure was refined on F values using the full-matrix least-squares procedure.The non-hydrogen atoms were refined anisotropically, while the positions of hydrogen atoms were geometrically calculated and their positional and isotropic atomic displacement parameters were not refined.Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary material with the deposition number CCDC 796256.Copies of the data can be obtained, free of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html.

Figure 1 .
Figure 1.Ortep view of compound 6b at the 50% probability level of ellipsoids.H atoms are drawn as small spheres of arbitrary radii.