Facile Synthesis of N-Substituted 4-Amino-6-methyl Resorcinols from Polysubstituted Cyclohexanone

Abstract

A novel synthesis of N-substituted 4-​amino-​6-​methyl resorcinols from polysubstituted cyclohexanone was developed. The reaction was performed in an easy ‘one-pot’, tandem manner with well-tolerated substituent on the nitrogen to give the desired compound in good to excellent yield. This highly efficient method will find broad application in the synthesis of some natural products and bioactive interesting compounds.

Key words

amino resorcinol - tandem process - aromatization - ­voglibose - carbasugar

• References and Notes

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• 11 N-Benzyl-2,4-bis(benzyloxy)-5-[(benzyloxy)methyl]aniline Hydrochloride(4a) – Typical Procedure To a solution of ketone 1 (2.0 mmol) in MeOH (10 mL) was added BnNH₂ (1.5 equiv) and MeSO₃H (10 mol%), the mixture was allowed to stir at 40 °C for 6.0 h. On completion of the reaction (TLC), the mixture was made basic with 0.1 M Na₂CO₃ and extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine and dried over anhydrous Na₂SO₄. The solvent was evaporated, the crude was further purified by column chromatography on silica gel, and then treated with HCl in EtOAc to give its hydrochloride as white powder; yield 960 mg (87%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.37 (s, 2 H, CH₂), 4.42 (s, 4 H, 2 × CH₂), 5.16 (s, 2 H, CH₂), 5.27 (s, 2 H, CH₂), 7.09 (s, 1 H, NH), 7.27–7.58 (m, 22 H, ArH). ESI-MS: m/z = 516.3 [M + H]⁺.
• 12 4-Amino-6-methylbenzene-1,3-diol (5a) – Typical Procedure Benzyl polyphenol hydrochloride (4a, 2.0 mmol) was dissolved in hydrochloric MeOH (10 mL), followed by the addition of 10% Pd/C (50 mg). The mixture was hydrogenated under hydrogen atmosphere in r.t. and stirred for 2 h whereupon the catalyst was removed by filtration, and the solvent was evaporated and dried to yield 5a as pale yellow powder, which was conserved under argon atmosphere and kept away from the light; yield 328 mg (93%). ¹H NMR (600 MHz, CD₃OD): δ = 0.54 (s, 3 H, Ar-CH₃), 4.94 (s, 1 H, ArH), 5.42 (s, 1 H, ArH). ¹³C NMR (600 MHz, CD₃OD): δ = 158.5, 151.5, 126.7, 118.3, 111.1, 104.5, 16.1. ESI-MS: m/z = 139.2 [M]⁺.