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Synlett 2017; 28(15): 2041-2045
DOI: 10.1055/s-0036-1588853
DOI: 10.1055/s-0036-1588853
letter
Highly Enantioselective Biginelli Reaction of Aliphatic Aldehydes Catalyzed by Chiral Phosphoric Acids
Further Information
Publication History
Received: 06 April 2017
Accepted after revision: 04 May 2017
Publication Date:
07 June 2017 (online)
Abstract
Several chiral phosphoric acids were evaluated as organocatalysts for the enantioselective Biginelli reaction of aliphatic aldehydes. With a chiral phosphoric acid derived from 3,3′-bis(3,5-di-tert-butyl-4-methoxyphenyl)-1,1′-binaphthalene-2,2′-diol, and after extensive optimization of the reaction conditions, the corresponding dihydropyrimidines were obtained in moderate to high yields with 73–87% ee by a three-component reaction of an aliphatic aldehyde, urea, and a β-keto ester.
Key words
Biginelli reaction - asymmetric catalysis - organocatalysis - chiral phosphoric acids - aldehydes - keto estersSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1588853.
- Supporting Information
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- 27 6-Methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates 7a–i; General Procedure A solution of urea (4a; 0.2 mmol), phosphoric acid 2f (0.02 mmol), and the appropriate aliphatic aldehyde 3 (0.24 mmol) in CH2Cl2 (2 mL) was stirred at 25 °C for 2 h, then the appropriate β-keto ester 5 (0.6 mmol) was added and the mixture was stirred at 25 °C for 10 d. Excess solvent was evaporated, and the resulting orange gum was purified by column chromatography [silica gel, hexane–i-PrOH (15:1)] to give a white crystalline solid. Methyl 6-Methyl-2-oxo-4-(2-phenylethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate (7a) White solid; yield 40 mg (73%, 85% ee); mp 190–191 °C; [α]D 20 +99.0 (c = 0.3, CH2Cl2); HPLC: Chiralpak AD-H, hexane–i-PrOH (90:10), 1.0 mL/min, 280 nm: t R (minor) = 9.86 min, t R (major) = 12.73 min. 1H NMR (600 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.29–7.26 (m, 2 H), 7.19–7.14 (m, 3 H), 5.68 (s, 1 H), 4.34 (dt, J = 7.8 Hz, 3.6 Hz, 1 H), 3.70 (s, 3 H), 2.79–2.74 (m, 1 H), 2.66–2.61 (m, 1 H), 2.29 (s, 3 H), 1.94–1.88 (m, 2 H). 13C NMR(150 MHz, CDCl3): δ = 166.3, 154.4, 147.1, 141.0, 128.5, 128.3, 126.0, 101.2, 51.3, 51.2, 38.2, 30.7, 18.7. HRMS: m/z [M + H]+ calcd for C15H19N2O3: 275.1390; found: 275.1398.