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DOI: 10.1055/s-0036-1589472
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
Publication History
Received: 23 September 2016
Accepted after revision: 14 November 2016
Publication Date:
08 December 2016 (online)
![](https://www.thieme-connect.de/media/synlett/201706/lookinside/thumbnails/st-2016-b0634-l_10-1055_s-0036-1589472-1.jpg)
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
- Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0036-1589472.
- Supporting Information
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References and Notes
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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 1a–g. For pharmacological experiments, analytical-grade samples of compounds 1a–g 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.
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