Continuous Synthesis of Hydantoins: Intensifying the Bucherer–Bergs Reaction

Dedicated to Professor Steven V. Ley on the occasion of his 70^th birthday

Abstract

A continuous Bucherer–Bergs hydantoin synthesis utilizing intensified conditions is reported. The methodology is characterized by a two-feed flow approach to independently feed the organic substrate and the aqueous reagent solution. The increased interfacial area of the biphasic reaction mixture and the lack of headspace enabled almost quantitative conversions within ca. 30 minutes at 120 °C and 20 bar even for unpolar starting materials. In addition, a selective N(3)-monoalkylation of the resulting heterocycles under batch microwave conditions is reported yielding potential acetylcholinesterase inhibitors.

Key words

continuous flow - process intensification - hydantoins - Bucherer–Bergs reaction - microwave-assisted organic synthesis

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• 22 General Experimental Procedure for the Continuous Bucherer–Bergs Reaction Feed A consisting of the carbonyl compound 1a–k dissolved in EtOAc was pumped with a flow rate of 70 μL min^–1 and merged in a T-shaped mixing unit with a second feed (430 μL min^–1) containing an aqueous solution of (NH₄)₂CO₃ (3.5 equiv) and KCN (1.5 equiv). The combined mixture was passed through a coil reactor made out of Hastelloy (16 mL internal volume, 32 min residence time) at 120 °C and 20 bar back pressure. To avoid precipitation of the corresponding hydantoin, the back pressure regulating unit was heated to 120 °C. The reaction mixture was collected in a sealed flask and subsequently acidified with concentrated HCl. Workup by extraction with EtOAc or crystallization afforded the respective hydantoins 2a–k in analytical purity. Analytical Data for Compound 2a Feed A: acetophenone (2.53 mmol, 5.0 M in EtOAc). Feed B: KCN (1.24 M), (NH₄)₂CO₃ (2.88 M) in H₂O. Isolation by extraction afforded the title compound in 91% yield (440 mg, 2.31 mmol) as a colorless solid; mp 197–199 °C. ¹H NMR (300 MHz, DMSO): δ = 10.77 (s, 1 H), 8.62 (s, 1 H), 7.50–7.46 (m, 2 H), 7.43–7.30 (m, 3 H), 1.66 (s, 3 H). ¹³C NMR (75 MHz, DMSO): δ = 177.42, 156.69, 140.37, 128.93, 128.26, 125.77, 64.35, 25.39.
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• 28 General Experimental Procedure for the Selective N(3)-Monoalkylation of Hydantoins A sealed 10 mL microwave process vial containing a mixture of the respective hydantoin (0.5–1.0 mmol), K₂CO₃ (1.1 equiv), and (5-bromopenthyl)trimethylammonium bromide (1.2 equiv) in MeCN (2 mL) was heated for 10–45 min at 120 °C using a single-mode microwave reactor. After cooling to r.t. the reaction mixture was concentrated. The organic material was dissolved in MeCN, and the inorganic salts were separated by filtration. Evaporation of the solvent resulted in a solid material which was carefully washed with cold EtOH before drying affording the respective N-substituted hydantoins 4a–k in analytical purity. Analytical Data for Compound 4a Reaction time: 10 min; yield: 66% (130 mg, 0.33 mmol) as colorless solid; mp 222–224 °C. ¹H NMR (300 MHz, DMSO): δ = 8.90 (s, 1 H), 7.49–7.31 (m, 5 H), 3.43–3.33 (m, 4 H), 3.25–3.19 (m, 2 H), 3.02 (s, 9 H), 1.68 (s, 3 H), 1.60–1.50 (m, 2 H), 1.25–1.15 (m, 2 H). ¹³C NMR (75 MHz, DMSO): δ = 175.85, 156.11, 140.06, 129.05, 128.43, 125.81, 65.46, 63.14, 52.60, 52.56, 52.52, 37.94, 27.54, 25.40, 23.42, 22.03. HRMS (APCI): m/z calcd for C₁₈H₂₈N₃O₂ ⁺ [M – Br^–]⁺: 318.217604; found: 318.217459.