Synlett 2016; 27(01): 83-87
DOI: 10.1055/s-0035-1560317
letter
© Georg Thieme Verlag Stuttgart · New York

Continuous Synthesis of Hydantoins: Intensifying the Bucherer–Bergs Reaction

Julia L. Monteiroa, b, Bartholomäus Piebera, Arlene G. Corrêab, C. Oliver Kappe*a
  • aInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
  • bDepartamento de Química, Universidade Federal de São Carlos, São Carlos, 13565-905, SP, Brazil
Further Information

Publication History

Received: 15 July 2015

Accepted after revision: 22 August 2015

Publication Date:
17 September 2015 (eFirst)

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

Supporting Information

 
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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 4ak 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.