Reaction of Acyclic Enaminones with Methoxymethylene Meldrum ’ s Acid . Synthetic and Structural Implications

* e-mail: silviodc@ufba.br Present address: Instituto de Química, Universidade Federal da Bahia, Campus de Ondina, 40170-290 Salvador BA, Brazil. # Dedicated to Professor Albert James Kascheres, a great mentor and pioneer in ciclopropenone chemistry in Brazil, on the occasion of his 60th birthday. Reaction of Acyclic Enaminones with Methoxymethylene Meldrum’s Acid. Synthetic and Structural Implications#


Introduction
The fascinating chemistry of enaminones and their derivatives has attracted the attention of numerous researchers due to their ambiphilic and ambident properties and their potential in the synthesis of heterocyclic compounds. 1In this context, the aza-annulation reaction of cyclic and acyclic enaminones has been extensively used in the preparation of a broad spectrum of nitrogencontaining compounds, 2 mainly in alkaloids 3 and conformationally constrained peptide analogues. 4ecause of these applications several protocols for the synthesis of enaminones have been developed. 5Among them, the solid support method developed by Braibante and co-workers 6 and its systematic use in the synthesis of pyrazoles and isoxazoles derivatives is noteworthy. 7hile the reaction of methoxymethylene Meldrum's acid (1) with cyclic enaminones has been documented (Scheme 1, reactions 1-4), 8 much less study has been carried out with 1 and acyclic enaminones.There is only a single paper describing two examples of reaction of 1 with enaminones 11 and 13a (Scheme 1, reactions 5-6). 8owever, the aza-annulation of derivatives 12 and 14a under pyrolysis conditions (Scheme 1, reaction 7) is not synthetically efficient because mixture of products and poor yields are obtained.In search for a general method of synthesis of derivatives 12 to 14 we undertook a study concerning the reactions of acyclic enaminones and methoxymethylene Meldrum's acid (1).In this paper we report the results of this study with emphasis on synthetic, mechanistic and structural implications.

Results and Discussion
Enaminones may act as an ambident nucleophile by reaction at the nitrogen and at the β-carbon.The reactions of enaminones and methoxymethylene Meldrum's acid depend on the N-amino substituent, Scheme 1. C-Adducts are obtained with NR 2 substituent (R = alkyl) and N-adducts with the NH 2 group.However, when we attempted the reaction of enaminone 13a with 1 under the literature condition 8 a low yield of the N-adduct 14a was obtained (36%, instead of the reportedly obtained 60% yield).Additionally, a small quantity of the C-adduct 18a was isolated (3.2% yield, Scheme 2), which was not previously reported.The spectral data of compound 14a here obtained were identical with those described. 8The 1 H NMR spectra contained a low field N-H (13.93 ppm) which suggests its participation in intramolecular hydrogen bonding.Despite the reportedly E-s-E configuration to 14a we assigned the Z-s-Z configuration to the N-adduct because E-s-E and Zs-Z configurational isomers of enaminones are well distinguished by typical N-H chemical shifts (E-isomer: 4.1-6.5 ppm; Z-isomer: 9.5-12.0ppm). 9Moreover, the structure of 14a was unambiguously confirmed by X-ray analysis and the Z configuration corroborated, as shown in Figure 1.
In addition, extension of the reported protocol 8 to other enaminones afforded complex mixtures.Better results were obtained when CH 2 Cl 2 was used as solvent instead of CH 3 CN (Scheme 2).With this modification N-and Cadducts 14a-b and 18a-b were obtained in a 2:1 ratio, respectively.With enaminone 13c only the C-adduct 18c was formed in good yield.
To our surprise, when we attempted the reaction of 1 with enaminone 13d a complex mixture was obtained, and the 2-pyridone 19d could be isolated in 28% yield (Scheme 3, reaction.1).Unfortunately, the pyridone 19d was an unstable solid that precluded its complete spectral characterization.However, its structure could be assigned by comparison of its IR and 1 H NMR spectra with analogue 19c (see Experimental).The formation of 19d may be visualized as occurring through the aza-annulation of the initial C-adduct of the reaction of 1 and 13d.To support this mechanistic proposal we decided to perform the thermolysis of the isolated C-adduct 18c.In this way, 18c was refluxed in toluene and the 2-pyridone 19c was obtained in good yield (Scheme 3, reaction 2).The structure of 19c was corroborated by analysis of a long-range heterocorrelation (COLOC) spectrum which showed correlation ( 3 J) of the hydrogen at C-4 with the carbonyl C-2 and with C-6 as well as the other correlations indicated in Scheme 4, which also presents the mechanistic pathway to 19c.Interestingly, in this thermal cyclization the typical CO 2 elimination from the methylene Meldrum's acid moiety was not observed. 10It should also be pointed out that the relative low temperature required to form the 2pyridones 19c-d makes this methodology synthetically attractive, contrasting with the literature pyrolysis condition for the N-adduct 14a. 8nderstanding how enaminones fit together in the solid state is of particular interest to recognize the relationships between structural features and pharmacological properties, e.g. the anticonvulsant activity of enaminones has been associated with the inter-and intramolecular NH...O, CH...O and CH...N hydrogen bonding in the threedimensional structure. 11To unambiguously assign the structure of the obtained enaminones and to gain insight into intra-and intermolecular interactions the crystal structures of 14a and 14b were determined, and several structural features emerged.As noted in Figure 1, which In conclusion, the reactions of acyclic enaminones and methoxymethylene Meldrum's acid afford N-and/or Cadducts and 2-pyridones were formed from the latter through an intramolecular aza-annulation.The scope, limitations and the application of the methodology here described in natural products synthesis is under investigation in our lab and will be reported opportunely.

Experimental
Melting points were determined on a Karl Kolb apparatus and are uncorrected.Infrared spectra were recorded as KBr discs on a FT-IR BOMEM MB100 instrument.NMR spectra were obtained for 1 H at 300 MHz and for 13 C at 75 MHz using a Varian Gemini 300 or a Bruker AC300P spectrometers at Instituto de Química, UNICAMP.Chemical shifts are reported in ppm units downfield from reference (internal TMS).MS spectra were measured on a SHIMADSU CG-MS QP-5050 spectrometer at 70 eV.Elemental analyses were performed on a 2400 CHN Perkin Elmer instrument at Instituto de Química, UNICAMP.Enaminones 13a-b, 6 13c, 13 13d, 6 Meldrum's acid 13 and methoxymethylene Meldrum's acid 13 were prepared according to known procedures.The single crystal X-ray data collections were carried out on a Nonius CAD-4 diffractometer at Departamento de Química, UFSC.