Synlett 2017; 28(06): 695-700
DOI: 10.1055/s-0036-1589472
letter
© Georg Thieme Verlag Stuttgart · New York

Intensified Microwave-Assisted N-Acylation Procedure – Synthesis and Activity Evaluation of TRPC3 Channel Agonists with a 1,3-Dihydro-2H-benzo[d]imidazol-2-one Core

Gema Guedes de la Cruz
a  Institute of Chemistry, University of Graz and NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria   Email: toma.glasnov@uni-graz.at
,
Barbora Svobodova
b  Institute of Biophysics, Medical University of Graz, Harrachgasse 21/IV, 8010 Graz, Austria   Email: klaus.groschner@medunigraz.at
,
Michaela Lichtenegger
b  Institute of Biophysics, Medical University of Graz, Harrachgasse 21/IV, 8010 Graz, Austria   Email: klaus.groschner@medunigraz.at
,
Oleksandra Tiapko
b  Institute of Biophysics, Medical University of Graz, Harrachgasse 21/IV, 8010 Graz, Austria   Email: klaus.groschner@medunigraz.at
,
Klaus Groschner*
b  Institute of Biophysics, Medical University of Graz, Harrachgasse 21/IV, 8010 Graz, Austria   Email: klaus.groschner@medunigraz.at
,
Toma Glasnov*
a  Institute of Chemistry, University of Graz and NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria   Email: toma.glasnov@uni-graz.at
› Author Affiliations
Further Information

Publication History

Received: 23 September 2016

Accepted after revision: 14 November 2016

Publication Date:
08 December 2016 (eFirst)

Abstract

Upon controlled microwave heating and using cyanuric chloride as a coupling reagent, an efficient amidation procedure for the synthesis of 1,3-dihydro-2H-benzo[d]imidazol-2-one-based agonists of TRPC3/6 ion channels has been developed. Compared to the few conventional protocols, a drastic reduction in processing time from ca. 2 days down to 10 minutes was achieved accompanied by significantly improved product yields. The robustness of the method was confirmed by 18 additional examples including aromatic, aliphatic, and heterocyclic amines and acids. The obtained agonists were screened for biological activity at 1 μM concentration and few structure–activity relations have been established.

Supporting Information

 
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  • 10 General Experimental Procedure for Microwave-Assisted TCT-Acylation To a stirred mixture of a corresponding acid (0.819 mmol, 1 equiv), cyanuric chloride (90.5 mg, 0.491 mmol, 0.6 equiv), dry pyridine (99.1 mg, 1.23 mmol, 1.5 equiv), and dry MeCN (4.5 mL) in a 5 mL Pyrex microwave vial, equipped with a magnetic stir bar, the corresponding amine (0.983 mmol, 1.2 equiv) was added after initial stirring at r.t. for 5 min. The reaction mixture was then crimped with a Teflon septum, stirred for 10 s, and subjected to microwave heating for 5 min (fixed hold time) at 140 °C and subsequently cooled down to 40 °C. The resulting reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (with CHCl3 or a gradient of 0–10% MeOH in CHCl3) to afford amides 1ag. For pharmacological experiments, analytical-grade samples of compounds 1ag were additionally purified by the means of a semipreparative HPLC (see the provided Supporting Information). 1-(1-Octanoylpiperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (1a) Transparent oil; yield 177 mg (63%). 1H NMR (300 MHz, CDCl3): δ = 10.05 (br s, 1 H), 7.15–7.04 (m, 4 H), 4.90 (d, J = 13.1 Hz, 1 H), 4.60–4.52 (m, 1 H), 4.07 (d, J = 13.1 Hz, 1 H), 3.20 (t, J = 12.9 Hz, 1 H), 2.68 (t, J = 13.5 Hz, 1 H), 2.43–2.26 (m, 4 H), 1.93–1.88 (m, 2 H), 1.73–1.64 (m, 2 H), 1.40–1.25 (m, 8 H), 0.88 (t, J = 6.8 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 171.9, 155.1, 129.0, 128.2, 121.6, 121.3, 110.1, 109.4, 50.9, 45.4, 41.5, 33.6, 31.9, 29.6, 29.3, 25.6, 22.8, 14.2. HRMS (APCI): m/z calcd for C20H30N3O2 [M + H]+: 344.2332; found: 344.2334.