Reactions of diethyl 2-(ethoxymethylene)malonate with 2-cyanoacetanilides: unexpected transfer of the ethoxymethylene moiety

A sodium ethoxide catalyzed reaction of N -substituted cyanoacetanilides 1a-f with diethyl 2-(ethoxymethylene)malonate 2 unexpectedly leads to the corresponding 2-amino-5-cyano-6- oxo-N ,1-diaryl-1,6-dihydropyridine-3-carboxamides 3a-f , while the expected 5-cyano-2-hydroxy-6-oxo-1-aryl-1,6-dihydropyridine-3-carboxylates 4a-f were observed only as minor products.


Introduction
The synthesis of 2-pyridone derivatives is of a continued interest in the field of heterocyclic chemistry.Several topical reviews have appeared in the literature over the last years about the synthesis of the 2-pyridone ring. 1 These heterocycles attracted attention because of their applications as bioactive compounds for example as a promising class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), 2 as antibacterial, 3 antifungal 4 and cardiotonic agents. 5oreover, such derivatives have recently become important due to their structural similarity to nucleosides. 6Also, 2-pyridones were used as ligands for the late 3d-metals. 7Thus, the development of novel methods for the synthesis of the 2-pyridone ring is of topical interest.
Our efforts in this area are focused on the synthetic routes where the 2-pyridone ring is assembled from a C-1 synthon and two methylene active components. 8Application of N-substituted cyanoacetamides as CH-acids 9 in such schemes allows introduction of an

Results and Discussion
Reactions of N-substituted cyanoacetamides 1a-f with DEEMM 2 in EtOH in the presence of 1.0 equiv of EtONa at room temperature resulted in the isolation of diaryl derivatives 3a-f as major products instead of the expected ethyl carboxylates 4a-f (Scheme 1).The compounds 3a-f were isolated upon filtration in moderate to good yields after recrystallization (Table 1, Method A), however, the formation of the expected products 4a-f was also detected by LC/MS of the crude products 3a-f.Application of weaker bases (N-methylmorpholine, Et3N in EtOH or DMF) at room or elevated temperatures resulted in recovery of the starting materials.The use of DEEMM 2 taken in excess did not increase the yield of the minor products 4a-f, however, excess of sodium ethoxide allowed isolation of two representatives of the minor ester derivatives 4c,e in small yields from the mother solutions (Table 1).To obtain the desired products 4a,b we also attempted to use dimethylformamide dimethylacetal (DMFDMA) as C-1-synthon in threecomponent or one-pot step-by-step reaction format (with initial interaction between diethyl malonate and DMFDMA).All these attempts resulted in the isolation of the known adducts 5a,b 13 which did not react with diethyl malonate.
The application of smaller amounts of sodium ethoxide (0.5 equiv) led to the isolation of open chain products 6 (Scheme 2) in the mixture with their isomers of type 3.One representative of such isomeric compounds bearing an ortho-methoxy group 6c was successfully isolated.This compound is stable enough in DMSO-d6 during NMR measurements and could be purified by recrystallization.Heating of 6c in EtOH in the presence of sodium ethoxide resulted in the formation of 2-pyridone 3c in 80% yield.

Scheme 2
We found in the literature only a single instance 14 where a representative of the heterocyclic class 3 was obtained.Thus, to examine a possible alternative synthetic route to such molecules, and also to model one of the possible reaction stages of their formation from cyanoacetamides 1a-f and DEEMM 2 (Scheme 1) we utilized ethoxymethylene derivatives 7a-c (Scheme 3).Thus, their reaction with cyanoacetamides 1a-c under the same conditions resulted in formation of the desired derivatives 3a-c in very high yields (Table 1, Method B) without additional purification.

Scheme 3
Comparing Methods A and B one should take into account that the Method B required the initial synthesis of ethoxymethylene compounds 7a-c which were obtained in 65-90% isolated yields (see Experimental Section for details).
The 1 H NMR spectrum of compound 6c shows 3-CH proton signals at 8.28 ppm (compared to 3c, the corresponding singlet of 4-CH proton is at 7.94 ppm) and it contains also one range of proton signals of two equivalent aromatic substituents with a double integral intensity, whereas two aromatic rings of 3c differ in their proton chemical shifts.The amide protons of this compound appear in the usual area for them (8.66, 9.45 ppm), for the open chain isomer 6c one broad signal of its amide groups is located at 8.20 ppm probably due to the efficient conjugation and distribution of the charge in the anion form.The signal of 2-/4-CH proton is absent in the 1 H NMR spectrum of 6c in DMSO-d6 probably due to fast deuterium exchange.However in the 13 C NMR spectrum, a signal at 75.13 ppm can be obviously assigned to the 2-/4-CH carbons.This signal does not appear in the DEPT also demonstrating the mobility of this CH proton.

Possible reaction mechanisms
In view of the chemical behavior of DEEMM in the reactions with 2-cyanoacetanilides and the determined structures of the products 3, 4 and 6 one can consider two possible reaction pathways to the diaryl derivatives 3 (Scheme 4).The first suggests initial transfer of the ethoxymethylene moiety from DEEMM onto the active cyanomethylene compound 1 giving ethoxymethylene derivative 7 (analogous behavior was previously observed for DMFDMA adducts, 10 see also Schemes 1 and 3), which then reacts with another molecule 1 giving an open chain kinetic product 6 which after base catalyzed cyclization gives pyridone 3 (Route A).

Scheme 4
On the other hand, the formation of the minor product 4 proceeds via conjugate addition of the methylene active nitrile 1 to DEEMM.Intermediate 8 that meanwhile may undergo a Michael addition of the second molecule of 1, as showed on the Scheme 4, and after elimination of diethylmalonate finally results in formation of pyridone 3 (Route B).

Conclusions
Interaction of N-substituted cyanoacetamides 1a-f with DEEMM 2 in the presence of sodium ethoxide (1.0 equiv) at room temperature proceeds via two competing reaction pathways resulting in formation of diaryl derivatives 3a-f and admixtures of ethyl carboxylates 4a-f.Application of lower amounts of sodium ethanolate was favorable for isolation of acyclic intermediate 6c which was transformed into the corresponding pyridone 3c.

Experimental Section
General.The IR spectra were recorded on a FIR «Spectrum One» (PerkinElmer) in KBr.Melting points were determined on a Koeffler apparatus. 1H and 13 C NMR spectra were recorded on Varian Mercury VX-200 and Bruker Avance DRX 500 spectrometers in DMSO-d6 with TMS as an external standard.LC/MS data were recorded using chromatography/mass spectrometric system "Agilent 1100 Series" equipped with a diode-matrix and massselective detector "Agilent LC/MSD SL" with Zorbax SB-C18, 1.8 μm, 4.6 mm × 15 mm column using eluents: A, acetonitrile/water (95:5), 0.1% TFA; B, water (0.1% of TFA) and eluent flow: 3 mL/sec.Volume of the injected sample was 1 μL.UV detectors were operated at 215, 254, and 265 nm.Chemical ionization under atmospheric pressure was used in MS detector.Ionization mode: simultaneous scanning of positive and negative ions in the mass range of 80-1000 m/z.Elemental analysis was carried out on an EuroVector EA-3000 instrument.TLC was performed on Silufol UV-254 plates with eluent system: acetone-hexane (3:5), visualization: UV light, iodine vapors.

X-Ray structure determination for (3a)
Crystal data: C19H14N4O2, M 330.34, monoclinic, space group P21, а= 9.2159( 14), b = 8.2387 (12), c = 10.8726(17)Å, = 93.054(5),V = 824.4(2)Å 3 , Z = 2, dc = 1.331 g•cm -3 ,  0.090 mm -1 , F(000) 344 crystal size ca.0.40  0.28  0.13 mm.All crystallographic measurements were performed at room temperature on a Bruker Smart Apex II diffractometer operating in the  and  scans mode.The cell parameters were obtained from the least-squares treatment of 1918 reflections in the  range of 2.82-26.55.The intensity data were collected within the range of 2.82    29.49 using Mo-K radiation ( = 0.71078 Å).The intensities of 5873 reflections were collected (3856 unique reflections, Rmerg = 0.0217).Data were corrected for Lorentz and polarization effects.The SADABS absorption correction (the ratio of minimum to maximum apparent transmission is 0.653252) was applied.The structure was solved by direct methods and refined by the full-matrix least-squares technique in the anisotropic approximation for non-hydrogen atoms using the SHELXS97 and SHELXL97 programs. 16,17All hydrogen atoms were refined isotropically.In the refinement 3856 independent reflections (3026 reflections with I  (I)) were used.Convergence was obtained at R1 = 0.0597 and wR2 = 0.0962, GOF = 1.003 for all reflection and R1 = 0.0420 and wR2 = 0.0867, GOF = 1.003 for observed (282 parameters; observed/variable ratio 10.7; the largest and minimal peaks in the final difference map 0.13 and -0.31 e/Å 3 , weighting scheme is as follows:  = 1/[ 2 (Fo 2 ) + (0.0442P) 2 + 0.0316Р], where Р = (Fo 2 + 2Fc 2 )/3), Flack parameter 0.0 (12), thus absolute configuration was not determined because of absence of heavy atoms.Full crystallographic details have been deposited at Cambridge Crystallographic Data Centre (CCDC).Any request to the CCDC for these materials should quote the full literature citation and reference number CCDC 784198.-f, 4c,e) and (6c).Method A Sodium (0.005 mol) was dissolved in 2 mL of abs.EtOH.To this solution the appropriate CHacid 1a-f (0.005 mol) was added and stirred for 5 min at rt. DEEMM 2 (0.005 mol) was added to the mixture and stirred for 1 h at rt.The precipitate 3 was filtered off and washed with ethanol and hexane, crystallized from DMF (for 3a-c,f) or butanol-1 (for 3d,e).Compounds 4c,e were isolated following this procedure with a use of 0.01 mol of EtONa.To the filtrate from precipitation of 3 1 mL of 10% KOH aqueous solution was added and the precipitates 4c,e was left overnight was filtered off and washed with ethanol and hexane.Recrystallisation was performed from butanol-1 4c or DMF 4e.Compound 6c was obtained in 71% yield following method A using 2.5 mmol sodium ethanolate.The product was recrystallized from acetone.

Scheme 1 Table 1 .
Isolated yields of the synthesized compounds