Convenient Synthesis and Anticancer Activity of Bis(aryl)alkanes and Bis(indolyl)methane Alkaloid Analogs
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onvenient Synthesis and Anticancer Activity of Bis(aryl)alkanes and Bis(indolyl)methane Alkaloid Analogs L. Qia and L. Xiaoa,* a Jiangsu
Vocational College of Medicine, Jie Fang South Road 283th, Yancheng, 224000 China *e-mail: [email protected] Received July 28, 2020; revised August 18, 2020; accepted September 7, 2020
Abstract—An efficient metal free high yield method of synthesis of bis(indolyl)methanes (BIMs) and bis(aryl)alkanes analogs in the presence of B(C6F5)3 by condensation of primary amines with pyruvates has been successfully developed. Some analogs of BIMs display good in vitro antitumor activity, screened by MTT assay. Compound 3b demonstrates the best anti-cancer activity against lung carcinoma cell A549 cells with IC50 of 4.52 μM. Keywords: bis(indolyl)methanes analogs; metal free; primary amines; pyruvates; antitumor
DOI: 10.1134/S1070363220100217 INTRODUCTION Bis(indolyl)methane derivatives (BIMs) as well as bis(aryl)alkane moieties demonstrate various types of biological and pharmacological activities, including antibacterial, anti-inflammatory [1], and anti-cancer [2]. Subsequently, a big number of practical methods of synthesis of BIMs has been reported, using Lewis acids, heteropoly acids, solid acids, ionic liquids, metal complexes, or biocatalysts [3–5]. Though some of such approaches proved to be efficient, some drawbacks still limited their application, among those were long reaction time, expensive or toxic metal ions, harsh acidity, and high temperature [3]. Most of the methods gave an accesses to the covalent C–C bond between C(sp2) of indoles or pyrroles and the acceptors, and only few catalytic protocols of activation of primary amines led to formation of covalent C–N bond (Scheme 1). Therefore, a demand of mild, efficient, metal-free catalytic method for various BIMs or bis(aryl)alkanes analogs was of considerable importance. B(C6F5)3, (Frustrated Lewis Pairs, FLPs) [6] has been successfully applied to several important organic transformations as a Lewis acid catalyst without any metal ion involved, including hydrogenation, hydrosilylation of unsaturated organic functional groups, dehydrogenation, polymerization, and some more [7–9]. In general, B(C6F5)3 as a strong Lewis acid, is able to activate an imine via π-coordination to the C–N double bonds. Accordingly, B(C6F5)3 is used as a π-Lewis acid activating
the imine to facilitate addition of primary amines leading to novel BIMs and bis(aryl)alkanes derivatives. Herein we report for the first time application of B(C6F5)3 as an efficient metal-free catalyst activating primary amine and leading to diverse BIMs and bis(aryl)alkanes analogs (Scheme 1, c). RESULTS AND DISCUSSION Initially, the process conditions were optimized for the reaction of tryptamine with methyl pyruvate (Table 1). Some solvents were tested in the presence of 5 mol % of B(C6F5)3, and it was found that 72% yield of 3a was obtained in DCM at room temperature (Table 1, entry 4). When the same reaction was carried out in DCM at 40°C, the desired product was synthesi
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