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Eco-friendly and Enantiospecific Biginelli Synthesis Using (+)-Myrtenal as the Substrate – An Impeccable and Unequivocal Analysis of the Product

Author(s):

Luiza Albino Dias Benincá, Carolina Bastos Pereira Ligiéro, Jonas da Silva Santos, Joel Jones Junior* and Flavia Martins da Silva   Pages 1 - 7 ( 7 )

Abstract:


Background: We found an excellent review in the literature of the Biginelli reaction that addresses the methodologies for obtaining enantiopure dihydropyrimidinones (DHPMs). In 1992, optically pure DHPMs were obtained by fractional crystallization of the diastereomeric ammonium salt derivative with (S)-(-) and (R)-(+)--methylbenzylamine and by other chiral resolution techniques, such chiral high-performance liquid chromatography (HPLC). Asymmetric syntheses of these compounds are also found in the literature. The main strategy uses acid catalysts such as organophosphates, organometallic complexes, amines and diamines, nanocomposites, and chiral ionic liquids, e.g., L-prolinium sulfate (Pro2SO4).

Objective: To study the Biginelli reaction with a chiral aldehyde.

Methods: A mixture of ethyl acetoacetate (0.26 g, 3 mmol), urea (0.18 g, 3 mmol) and ethyl lactate (EL) (1 mL) is left under heating at 70 °C and stirring for 1 h. Next, (-)-(1R)-myrtenal (0.45 g, 3 mmol) is added, and the medium is heated for 5 h more until a white solid forms. Ten millilitres of distilled water is added, and the product is extracted with CH2Cl2 (3 x 4 mL). The solvent is evaporated, and the product is recrystallized from ethanol-water. Results: (+)-Myrtenal was used as a chiral substrate for a study that led to ethyl (R)-4-((1R,5S)-6,6-dimethylbicyclo [3.1.1]hept-2-en-2-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate by the Biginelli synthesis using EL as a green solvent. The result is the first example of the enantiospecific Biginelli reaction. The product was exhaustively characterized by several physical analysis methods, i.e., 1H, 13C and 2D nuclear magnetic resonance (NMR) spectroscopies, infrared (IR) spectroscopy, mass spectrometry (MS), and high-resolution MS (HRMS), and its structure was unequivocally elucidated by X-ray crystallography.

Conclusion: Compound (4R)-4-(6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-6-methyl-2-oxo-1,2,3,4- tetrahydropyrimidine-5-ethyl carboxylate is the first example of the enantiospecific Biginelli reaction. In addition, the process has the advantage of using EL as a green solvent. The product was characterized by 1H, 13C, and 2D NMR and IR spectroscopy, MS, HRMS, and X-ray crystallography.

Keywords:

Biginelli, green chemistry, green solvent, ecofriendly, myrtenal, enantiospecific

Affiliation:

Síntese Orgânica Ambiental SOA - Dept. Química Orgânica - Instituto de Química – UFRJ - CP 68.584, Rio de Janeiro, RJ, Síntese Orgânica Ambiental SOA - Dept. Química Orgânica - Instituto de Química – UFRJ - CP 68.584, Rio de Janeiro, RJ, Síntese Orgânica Ambiental SOA - Dept. Química Orgânica - Instituto de Química – UFRJ - CP 68.584, Rio de Janeiro, RJ, Síntese Orgânica Ambiental SOA - Dept. Química Orgânica - Instituto de Química – UFRJ - CP 68.584, Rio de Janeiro, RJ, Síntese Orgânica Ambiental SOA - Dept. Química Orgânica - Instituto de Química – UFRJ - CP 68.584, Rio de Janeiro, RJ



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