Synthesis of some new diarylmethanes by McMurry coupling reaction: characterization and antibacterial activity

Diarylmethanes (DAMs) and triarylmethanes (TAMs), molecules bearing two or three aryl groups (phenyls or heterocycles) bonded to a central carbon atom, have numerous applications. The biological and therapeutic relevancy of this class of molecules has been demonstrated for various applications in the field of antimicrobials, infectious, cardiovascular and nervous system disorders, genital tract diseases, estrogen-related disorders and bone remodeling. These interesting compounds have also been used as starting materials for the development of high value-added molecules. We report here the synthesis of two new diarylmethanes using a McMurry coupling reaction as well as their antibacterial evaluation.


Introduction
Di-and tri-arylmethanes have attracted much attention as a result of their unique structural and physical properties and applications in organic chemistry and as interesting scaffolds presented in biological active compounds [1][2].
The feature of triarylmethane compounds comes from the three aryl groups bonded to a sp3 hybridized central carbon atom bearing a hydrogen atom. Compounds containing two aryl groups connected by a single carbon atom are considered as diarylmethanes.

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Mol2Net, 2018, 1(Section A, B, C, etc.), 1-x, type of paper, doi: xxx-xxxx 2 Triarylmethane scaffolds are biological and therapeutical relevancy in several areas such as antimicrobials, anticancer cardiovascular and nervous system disorders and bone remodeling. They have been used as like leuco dyes, pH indicators, photochromic agents, fluorescent probes and they also have many applications in materials science [1][2][3][4][5][6][7]. Diarylmethanes based derivatives have played an essential role in the development of supramolecular chemistry and specially in the synthesis of supramolecular compounds like calixarenes and pillararenes. Furthermore, diarylmethanes have shown a major role in medicinal chemistry as GABAA receptor modulators [8], anticancer and antibacterial compounds [9][10]. Diarylmethane scaffold is mainly obtained by Friedel-Crafts alkylation of the corresponding benzyl alcohols with another arene, metalcatalyzed cross coupling of aryl halides with benzyl nucleophiles, metal catalyzed cross coupling of benzyl halides with aryl nucleophiles and C-C bond formation between tosyl hydrazones and aryl boronic acids [1]. Considering this perspective, we presented in this paper the synthesis of two diarylmethanes using a McMurry cross coupling reaction. This coupling procedure has acquired great importance in organic synthesis particularly in the preparation of sterically hindered alkenes through homocouplings and in the construction of cycloalkenes with ring sizes ranging from 3 to 72 via intramolecular couplings. The utility of McMurry coupling reaction have been also highlighted as the key step in numerous syntheses of natural products [11]. We describe herein the synthesis of two new diarylmethanes derivatives: 4-methoxyphenyl-2arylvinyl-pyridine and its ferrocenyl analogue and the preliminary evaluation of their antibacterial activity.

Synthesis of diarylmethanes
Diarylmethanes were prepared via a McMurry coupling reaction. General synthetic methods to obtain the target compounds are outlined in Scheme 1. The first detailed synthesis has been described by Sylla-I-V and co-workers in 2015. The (4-methoxyphenyl)(pyridin-2-yl)methanol 2 has been prepared by a lithium-bromine exchange following the procedure described by Seto et al. 2004 [12], from 2-bromopyridine and panisaldehyde in anhydrous THF. The desired carbinol 2 was isolated in 53% yield. This average yield could be explained to a certain extent by the formation of the by-product 6 formed by the reaction of 2-bromopyridine with two molecules of p-anisaldehyde ( Figure 1).

Figure 1:
The diol 6 formed during the lithiumbromine exchange reaction.
The aryl ketone 3 was synthesized from the carbinol 2 in excellent yield (98%) via a basepromoted aerobic oxidation using air as a free and clean oxidant [12,13]. The key step to obtain the desired olefin intermediates involved a McMurry cross-coupling reaction between the ketone 3 and the corresponding aldehydes (benzaldehyde or ferrocenecarboxaldehyde) to afford the desired compounds 4 and 5 in two separable E and Z isomers (24% and 23% yields respectively for compound 4 and 30% and 49% yields respectively for compound 5). After the preparation of the Zn/TiCl4 suspension, the reaction occurs in 8 to 10 minutes. Nevertheless, the yields can decrease because of the probable competition between the Mol2Net, 2018, 1(Section A, B, C, etc.), 1-x, type of paper, doi: xxx-xxxx 3 formation of the desired cross-coupled product and the two homo-coupled compounds 14].

Biological studies
Compounds 4 and 5 were screened for antibacterial activity against Gram-positive and Gram-negative pathogens.

Materials:
All reagents were obtained from commercial sources unless otherwise noted and used as received. All reactions were monitored by analytical thin layer chromatography (TLC). TLC was performed on aluminium sheets percolated silica gel plates (60 F254, Merck). TLC plates were visualized using irradiation with light at 254 nm or in an iodine chamber as appropriate.  Figure 2. Convention adopted to assign signals of 1 H and 13 C spectra.

methoxyphenyl-2-ferrocenyl-vinylpyridine 5
To a suspension of zinc (55.5 mmol, 3.63 g) in dry THF (60 mL) under argon was added dropwise TiCl4 (37.0 mmol, 4.08 mL). The reaction mixture was stirred during 2 h at 85 °C. A solution of ferrocenecarboxaldehyde (9.25 mmol, 1.98 g) and (4-methoxyphenyl) (pyridin-2-yl)methanone 3 (9.71 mmol, 2.071 g) in THF (30 mL) was then added dropwise via a syringe. The reaction mixture was stirred during 8 min and was controlled by TLC. The reaction was cooled to room temperature and then poured into the water (100 mL) and extracted with CH2Cl2 (3 * 150 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered and concentrated. The oily crude was purified by flash column chromatography on silica gel using a gradient system (cyclohexane/EtOAc 98:2 and then 95:5) to afford the 2-(1-(4-methoxyphenyl)-2 ferrocenylvinyl) pyridine 5 in two separable E and Z isomers. E Isomer 5a: 1. were dissolved in dimethylsulfoxide (DMSO). Serial two fold dilutions of each sample to be evaluated were made to yield volumes of 100 μL per well with final concentrations ranging from 100 to 12.5 μg/mL. 100 μL of bacteria suspension with a concentration of 107 CFU/mL were added to each Mol2Net, 2018, 1(Section A, B, C, etc.), 1-x, type of paper, doi: xxx-xxxx 6 well. Negative control wells contained bacteria only in LB broth medium. After incubation at 30°C for 16 h, the minimal inhibitory concentrations (MICs) were recorded as the lowest concentration of compound in the medium that showed no microbial growth. 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) was added to the wells to facilitate reading of the plates. In case of microbial growth, MTT turns to blue, otherwise the medium remains yellow. Solvent medium and positive growth controls were also run simultaneously. Then from each tube, one loopful was cultured on plate count agar and incubated for 24 h at 30 °C. The lowest concentration of the compound supporting no colony formation was defined as the MBC.

Conclusions
We have been involved in the design, synthesis and bioevaluation of new diarylmethanes derivatives 4 and 5 (Fig. 2) using a McMurry coupling reaction. The structural pharmacophore was based on a diarylmethane skeleton containing ferrocene and benzene rings, and compounds exhibited a good antibacterial activity in vitro. In order to optimize the antimicrobial activity of DAMs, we currently investigated the substitution of the aryl group by others aromatic rings and the introduction of the functionalization will be reported in due course.