Reaction of acyclic enaminones with methoxymethylene meldrum's acid: synthetic and structural implications

J. Braz. Chem. Soc., Vol. 14, No. 1, 107-112, 2003. Printed in Brazil - ©2003 Sociedade Brasileira de Química 0103 - 5053 $6.00+0.00 a, a b b Silvio Cunha *, Viviane C. da Silva , Hamilton B. Napolitano , Carlito Lariucci and Ivo Vencato a b b Instituto de Química, Instituto de Física, Universidade Federal de Goiás, CP 131, 74001-970 Goiânia - GO, Brazil A reação de enaminonas com o derivado metoximetilênico do ácido de Meldrum forneceu N-adutos e/ou C-adutos das enaminonas, em rendimentos moderados a bons. A regioquímica da reação se revelou dependente do substituinte do nitrogênio da enaminona, e o C-aduto formado é precursor para 2-piridonas. A análise da difração de raios X de dois N-adutos revelou que estes adutos possuem a configuração Z-s-Z. The reaction of acyclic enaminones with methoxymethylene Meldrum’s acid afforded N-adduct and/or C-adduct of enaminones in moderate to good yields. The regiochemistry of this reaction depends on the N-amino substituent of the enaminone. The C-adduct is a precursor to 2-pyridones. X-ray analysis of two N-adducts were investigated and the Z-s-Z configuration assigned. Keywords: enaminones, Meldrum’s acid, aza-annulation, 2-pyridone 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.1 In 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. 4 Because of these applications several protocols for the synthesis of enaminones have been developed.5 Among them, the solid support method developed by Braibante and co-workers6 and its systematic use in the synthesis of pyrazoles and isoxazoles derivatives is noteworthy.7 While 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 * e-mail: 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. enaminones 11 and 13a (Scheme 1, reactions 5-6). 8 However, 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 NR2 substituent (R = alkyl) and N-adducts with the NH2 group. However, when we attempted the reaction of enaminone 13a with 1 under the literature condition8 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.8 The 1H NMR spectra contained a low field N-H (13.93 ppm) which suggests its participation in intramolecular hydrogen bonding. Despite Article Reaction of Acyclic Enaminones with Methoxymethylene Meldrum’s Acid. Synthetic and Structural Implications# 108 Cunha et al. J. Braz. Chem. Soc. Scheme 1. 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: 9.5-12.0 ppm).9 Moreover, 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 protocol8 to other enaminones afforded complex mixtures. Better results were obtained when CH2Cl2 was used as solvent instead of CH3CN (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 1H 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 (3J) 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 CO2 elimination from the methylene Meldrum’s acid moiety was not observed.10 It 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.8 Understanding how enaminones fit together in the solid Vol. 14, No. 1, 2003 Reaction of Acyclic Enaminones with Methoxymethylene Meldrum’s Acid 109 Scheme 2. Scheme 3. Figure 1. X-ray crystallographic structures of compounds 14a (top) and 14b (bottom). Displacement ellipsoids are shown at the 30% probability level. Only the H-atoms involved in H-bonds are shown with arbitrary size. The intramolecular H-bonds are shown with broken lines. Scheme 4. 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 th (...truncated)