Synthesis and tautomeric studies of enamines from 1-(n-Hexyl)-3-methyl-2-pyrazolin-5-one

ARTICLE   Synthesis and tautomeric studies of enamines from 1-(n-Hexyl)-3-methyl-2-pyrazolin-5-one     Julio Belmar*, I; Fredy R. PérezII; Joel AldereteI; Celia ZúñigaI IDepartment of Organic Chemistry, Faculty of Chemical Sciences, Universidad de Concepción. Víctor Lamas, 1290, Casilla 160-C, Concepción, Chile IIDepartment of Chemistry, Faculty of Health Sciences, Universidad Privada Antenor Orrego, Av. América Sur, 3145, Monserrate, Trujillo, Perú     ABSTRACT 1-(n-Hexyl)-3-methyl-2-pyrazolin-5-one was acylated with acid chlorides. Condensation of acyl derivatives with primary amines afforded enamines. According to the 1H and 13C NMR data, the acyl derivatives have mainly a 4-acylpyrazol-5-ol structure with intramolecular hydrogen bond, and the 4-aminomethylene derivatives exist predominantly in the enamine form stabilized by the same type of interaction. Keywords: pyrazolones, alkylpyrazolones, acylation, acylpyrazolones, enamines RESUMO 1-(n-Hexil)-3-metil-2-pirazolin-5-ona foi acilada com cloretos de acidos e a condensação com aminas primárias forneceu uma série de enaminas. De acordo com os dados de RMN de 1H e 13C, os derivados acilas têm principamente uma estrutura 4-acilpirazol-5-ol com ligação de hidrogênio intramolecular e os derivados 4-aminometilenos existem predominantemente na forma de enamina estabilizada também por este tipo de interação.     Introduction Transition metals coordination complexes using a variety of polydentate ligands are very important in several fields of science and technology.1-4 They can give a wide variety of model compounds, to mimic, simulate, or modify biological and physical properties.5,6 An important number of the ligands that have been reported to date are Schiff bases7-10 or b-ketoenamines11,12 that are usually obtained from salicylaldehyde or b-dicarbonyl compounds.12,13 Other reagents have been almost completely neglected. 4-Aminomethylene derivatives of pyrazolin-5-ones (Figure 2D) have been known for almost a century14 and have been used as ligands to obtain metal complexes.15 They are not as well known as metal complexes of acylpyrazolones though.16 Pyrazolone derivatives usually reported do not have good solubility in solvents such as hexane, ethyl acetate, chloroform, acetone, tetrahydrofurane and ethanol, because in most cases they have a phenyl ring at N-1. In order to find better applications for these kinds of compounds, solubility must be improved. Attaching an alkyl chain at position 1 rather than an aryl ring would help to overcome this drawback. This approach faces the facts that very few alkylhydrazines are commercially available and that there is a lack of convenient procedures17 to synthesize them. Despite of these problems, alkylation of 3-methyl-18 and 3-phenyl-19 pyrazol-5-one has been reported. These 1-alkylpyrazolones underwent acylation,18 benzoylation20 and nitrosation21 in a similar way to their 1-phenyl homologues. Since little information on 4-aminomethylene derivatives of alkylpyrazolones is available, it was decided to study them. In this paper, besides the synthetic procedures, the structural features that have been found on characterizing these compounds are reported. In order to save time and chemicals, attention was focused on changing the acyl group and the amines, leaving the alkyl chain at N-1 unchanged; this procedure does not restrain the conclusions of this work. Therefore, 4-acyl-(1-n-hexyl)-3-methyl-5-pyrazolones and bidentate, tridentate and tetradentate 4-aminomethylene derivatives, some of them including a chiral center, are reported herein.         Results and Discussion The synthesis is outlined in Scheme 1. As previously described,18 alkylation of 3-methylpyrazol-5-one (1) takes place at N-1 to give 1-(n-hexyl)-3-methyl-2-pyrazolin-5-one (2). This compound was acylated with acyl halides in alkaline medium22,23 yielding 4-acyl-1-(n-hexyl)-3-methylpyrazol-5-ol (3). The yields of 4-acyl derivatives 3 were 70% (3a), 68% (3b) and 40 % (3c). Acylation with pivaloyl chloride afforded 1-(n-hexyl)-3-methyl-4-pivaloylpyrazol-5-ol (3d) only in a modest 10%, despite of the prolonged reaction time. Compounds 3 were used to prepare 4-aminomethylene derivatives. Thus, condensation with diamines afforded compounds 4, while condensation with monoamines afforded compounds 5. Compounds 4 are tetradentate ligands and compounds 5 are either tridentate or bidentate. In addition 1,2-diaminopropane and trans-1,2-diaminocyclohexane are chiral. However, they were used as racemic mixtures. Regarding the monoamines, a variety of them was used. Some of them were aliphatic, aromatics, aminoacids or aminoalcohols. Among them DL-alanine and l-(-)-2-aminobutanol were chiral. Table 1 summarizes reaction times and yields for 4-aminomethylene compounds 4 and 5. As it could be expected, in most cases yields were higher with monoamines than with diamines. It was also observed that yields diminished when the NH2 was bonded to a secondary carbon, for instance 4c and 4e. A sharp reduction in the yield of compound 4 resulted as ramification in the acyl group increased, for example 4a, 4d and 4f. No aminomethylene product was isolated from pivaloylpyrazolone (3d) under the same conditions. The reaction of compound 3a with o-phenylenediamine afforded compound 5a resulting from the condensation of just one amino group. The remaining amino group of compound 5a would become less nucleophilic. Compound 5a was treated with an extra equivalent of 3a, being recovered unchanged. With respect to the yields achieved in reactions with monoamines, they were not only a consequence of the nucleophilicity but of the reagents and products solubility in the reacting medium. When DL-alanine was used, the yield of reaction was very low indeed, probably due to the scarce solubility of the aminoacid in the reaction solvent. Compounds 5b and 5c separated easily as a solid material from the reacting mixture, being recovered in higher yields. The effect of increasing hindrance was also observed in the yields of compounds 5.         Prototropic tautomerism has been widely studied in 1-arylpyrazolones and derivatives24-26 but not in 1-alkyl homologues. Specifically the tautomerism of 1-aryl-4-acylpyrazolones has been the subject of various studies.27-35 Based upon 1H- and 13C-NMR studies, Kurkovskaya30 et al. concluded that in CDCl3 solution, and at low temperature, 4-acetyl- and 4-benzoyl derivatives are mainly present in the associated OH form (A') (Figure 1) with a minor portion of NH form (B). They also found that electronegative groups, at position 3 in the heterocycle, favors the free OH form (A).30 In the case of 4-acyl-(1-n-hexyl)-3-methyl-5-pyrazolones (3), the possible tautomers are the same as those shown in Figure 1. Relevant 1H-NMR and 13C-NMR chemical shifts of compounds 3a-d are summarized in Table 2. Data agrees with the exist (...truncated)