Facile synthesis of symmetrical bis(benzhydryl)ethers using p-toluenesulfonyl chloride under solvent-free conditions
© Brahmachari and Banerjee; licensee Springer. 2013
Received: 30 November 2012
Accepted: 26 January 2013
Published: 18 February 2013
The benzhydryl ether moiety is widely distributed in nature and constitutes a key structural motif in numerous molecules of significant biological potential and of prospective clinical uses. Solvent-free and cost-effective facile synthesis of symmetrical bis(benzhydryl)ethers is, thus, much desirable.
A simple and efficient method for the facile synthesis of symmetrical bis(benzhydryl)ethers directly from the corresponding benzhydrols has been developed using a catalytic amount of p-toluenesulfonyl chloride (5 mol%) at an oil bath temperature of 110°C under solvent-free conditions.
Operational simplicity, low reagent loading, high product yields, short reaction time, and solvent-free conditions are the notable advantages of the present method.
KeywordsBis(benzhydryl)ethers Benzhydrols p-Toluenesulfonyl chloride Solvent-free
The benzhydryl ether moiety is abundant in a number of naturally occurring and biologically active compounds as well as molecules of potential clinical uses [1–8]; this motif was also found as a partial structure in a few new chemical entities showing therapeutic activity as well . A number of reports are available describing the synthesis of molecules bearing this structural motif, which were shown to exhibit various pharmacological potentials such as non-nucleoside reverse transcriptase inhibition , anti-plasmodial and anti-trypanosomal action , monoamine uptake inhibition, anti-depressant and anti-parkinsonian activity [12, 13], and anti-histaminic  and anti-spasmodic  action. Naturally occurring symmetrical bis(benzhydryl)ethers are also known to show promising therapeutic potentials including significant anti-platelet aggregation efficacy . Very recently, application of such ether substructures in the total syntheses of a number of natural products has nicely been reviewed by Pitsinos et al. . Although there are a good number of reports on the synthetic methodology of diaryl ethers, there are only two such reports so far on bis(benzhydryl)ethers in the literature [18–20]; symmetrical bis(benzhydryl)ethers were conventionally synthesized from corresponding benzhydrols using 100% sulfuric acid in large excess [18–20] and p-toluenesulfonic acid in equivalent amount . Both of these earlier methods require the use of strong acids in relatively large excess. Under this purview, we have been motivated to undertake systematic planning to develop a convenient and efficient protocol for the conversion of benzhydrols into their bis(benzhydryl)ether derivatives.
Infrared spectra were recorded using a Shimadzu (FT-IR 8400S) Fourier transform infrared (FT-IR) spectrophotometer (Shimadzu, Kyoto, Japan) using KBr disc. 1H and 13C nuclear magnetic resonance (NMR) spectra were obtained at 400 and 100 MHz, respectively, using a Bruker DRX400 spectrometer (Bruker Instruments, Billerica, MA, USA) and CDCl3 as the solvent. Mass spectra (time-of-flight mass spectrometry (TOF-MS)) were measured on a Q-Tof Micro™ mass spectrometer (Waters MS Technologies, Manchester, UK). Elemental analyses were performed with an Elementar Vario EL III Carlo Erba 1108 micro-analyzer instrument (Carlo Erba Reagenti SpA, Rodano, Italy). Melting point was recorded on a Sunvic melting point apparatus (Sunvic, Glasgow, UK) and is uncorrected. Column chromatography was carried out over silica gel (60 to 120 mesh, Merck & Co., Inc., Whitehouse Station, NJ, USA), and thin layer chromatography (TLC) was performed using silica gel 60 F254 (Merck) plates.
Results and discussion
Optimization of the reaction conditions following Figure 1
Yield (%) a
43 (tosylate: 47)
7 (tosylate: 91)
Synthesis of symmetrical bis(benzhydryl)ethers using p -TsCl as reagent under solvent-free conditions following Figure 2
General procedure for the synthesis of symmetrical bis(benzhydryl)ethers (entries 1 to 7)
An oven-dried screw cap test tube was charged with a magnetic stir bar, benzhydrol (1 mmol), and p-toluenesulfonyl chloride (5 mol%). The tube was then evacuated and back-filled with nitrogen. The evacuation/backfill sequence was repeated two additional times. The tube was placed in a preheated oil bath at 110°C, and the reaction mixture was stirred vigorously. The progress of the reaction was monitored by TLC, and on completion, the reaction mixture was cooled to room temperature. The reaction mixture was extracted with dried ethyl acetate (10 ml), and the extract was then concentrated under reduced pressure; the residue was purified via column chromatography using silica gel (60 to 120 mesh) and petrol ether-ethyl acetate mixture. The structure of each purified symmetrical bis(benzhydryl)ethers was confirmed by analytical as well as spectral studies including FT-IR, 1H NMR, 13C NMR, and TOF-MS. Respective physical and spectral properties of bis(diarylmethyl)ethers are described below.
The spectral and analytical data of all the compounds including all new entries are given below (see also Additional file 1):
Bis(bis-phenylmethyl)ether (1): white solid, 86% yield, m.p. 106°C to 107°C (Lit. 105°C to 107°C . 107°C ). IR (ν max, KBr) cm-1: 3,057, 3,028, 2,953, 1,595, 1,489, 1,445, 1,250, 1,163, 1,098, 1,072, 1,029, 6,98. 1H NMR (CDCl3, 200 MHz, δ): 7.40 to 7.23 (m, 20H, Ar H), 5.41 (s, 2H, CH). 13C NMR (CDCl3, 100 MHz, δ): 142.28, 128.45, 127.51, 127.33, 80.05. TOF-MS: 373.44 ([M + Na]+). Anal. found: C, 89.13; H, 6.28. C26H22O requires C, 89.11; H, 6.33%
Bis[[1-(4-methylphenyl)-1-phenyl]methyl]ether (2): yellowish white, semi solid, 89% yield. IR (ν max, KBr) cm-1: 3,060, 3,025, 2,923, 2,852, 1,655, 1,460, 1,277, 1,124, 1,071, 824, 810, 699. 1H NMR (CDCl3, 400 MHz, δ): 7.6 (d, 4H, Ar H, J = 7.6 Hz), 7.53 to 7.45 (m, 8H, Ar H), 7.43 to 7.41 (m, 2H, Ar H), 7.34 (d, 4H, Ar H, J = 7.6 Hz), 5.63 (s, 2H, CH), 2.53 (s, 6H, CH3). 13C NMR (CDCl3, 100 MHz, δ): 142.82, 142.70, 139.59, 139.48, 137.26, 137.22, 129.33, 129.30, 128.57, 128.54, 127.53, 127.49, 127.46, 127.41, 127.34, 79.96, 21.37. TOF-MS: 401.05 ([M + Na]+). Anal. found: C, 89.89; H, 6.90. C28H26O requires C, 89.85; H, 6.92%
Bis[[1-(4-chlorophenyl)-1-phenyl]methyl]ether (3): white semi solid, 85% yield. IR (ν max, KBr) cm-1: 3,063, 3,029, 2,925, 2,854, 1,595, 1,490, 1,449, 1,259, 1,185, 1,086, 1,057, 843, 811, 700. 1H NMR (CDCl3, 400 MHz, δ): 7.31 to 7.30 (m, 8H, Ar H), 7.28 to 7.25 (m, 10H, Ar H), 5.33 (s, 2H, CH). 13C NMR (CDCl3, 100 MHz, δ): 141.49, 141.39, 140.65, 140.54, 133.37, 133.30, 128.69, 128.63, 128.60, 128.56, 128.48, 127.87, 127.81, 127.22, 127.13, 79.53. TOF-MS: 441.94 ([M + Na]+). Anal. found: C, 74.45; H, 4.83. C26H20Cl2O requires C, 74.47; H, 4.81%
Bis[[1-(4-bromophenyl)-1-phenyl]methyl]ether (4): white semi solid, 92% yield. IR (ν max, KBr) cm-1: 3,085, 3,062, 3,028, 2,924, 2,854, 1,602, 1,590, 1,486, 1,454, 1,290, 1,185, 1,107, 1,070, 1,028, 847, 793, 700. 1H NMR (CDCl3, 400 MHz, δ): 7.33 (dd, 4H, Ar H, J = 8.4, 5.2 Hz), 7.21 to 7.15 (m, 10H, Ar H), 7.12 (dd, 4H, Ar H, J = 8.4, 3.2 Hz), 5.23 (s, 2H, CH). 13C NMR (CDCl3, 100 MHz, δ): 141.43, 141.33, 141.20, 141.08, 131.68, 131.62, 128.94, 128.86, 128.70, 128.65, 127.94, 127.87, 127.26, 127.17, 121.60, 121.52, 79.61. TOF-MS: 528.74 ([M + Na]+). Anal. found: C, 61.49; H, 3.93. C26H18Br2O requires C, 61.44; H, 3.97%
Bis[bis(4-chlorophenyl)methyl]ether (5): white solid, 88% yield, m.p. 125°C to 127°C (Lit. 126°C to 127°C) [35, 36]. IR (ν max, KBr) cm-1: 3,031, 2,924, 1,594, 1,491, 1,410, 1,290, 1,188, 1,089, 1,013, 854, 824, 735, 726. 1H NMR (CDCl3, 200 MHz, δ): 7.31 (d, 8H, Ar H, J = 8.6 Hz), 7.23 (d, 8H, Ar H, J = 8.6 Hz), 5.29 (s, 2H, CH). 13C NMR (CDCl3, 75 MHz, δ): 139.72, 133.71, 128.82, 128.36, 78.97. TOF-MS: 509.12 ([M + Na]+). Anal. found: C, 63.94; H, 3.69; C26H18Cl4O requires C, 63.96; H, 3.72%
Bis[bis[4-fluorophenyl]methyl]ether (6): white solid, 91% yield, m.p. 88°C to 90°C. IR (ν max, KBr) cm-1: 3,069, 3,057, 2,925, 1,603, 1,507, 1,422, 1,408, 1,298, 1,225, 1,178, 1,155, 1,101, 1,029, 859, 837, 818. 1H NMR (CDCl3, 400 MHz, δ): 7.19 to 7.16 (m, 8H, Ar H), 6.94 to 6.88 (m, 8H, Ar H), 5.22 (s, 2H, CH). 13C NMR (CDCl3, 100 MHz, δ): 163.52, 161.07, 137.51, 137.48, 128.82, 128.74, 115.59, 115.38, 78.91. TOF-MS: 445.98 ([M + Na]+). Anal. found: C, 73.89; H, 4.28. C26H18F4O requires C, 73.93; H, 4.30%
Bis[[1-(4-methoxyphenyl)-1-phenyl]methyl]ether (7): colorless liquid, 90% yield. IR (ν max, KBr) cm-1: 3,062, 3,029, 2,953, 2,932, 2,906, 2,835, 1,510, 1,494, 1,451, 1,249, 1,171, 1,111, 1,080, 849, 819, 698. 1H NMR (CDCl3, 400 MHz, δ): 7.35 (d, 4H, Ar H, J = 7.6 Hz), 7.32 to 7.28 (m, 4H, Ar H), 7.27 to 7.24 (m, 6H, Ar H), 6.84 (d, 4H, Ar H, J = 8.4 Hz), 5.34 (s, 2H, CH), 3.77 (s, 6H, OCH3). 13C NMR (CDCl3, 100 MHz, δ): 158.97, 158.93, 142.72, 142.52, 134.53, 134.32, 128.67, 128.60, 128.35, 128.32, 127.30, 127.24, 127.17, 127.09, 113.80, 113.77, 79.43, 79.40, 55.26. TOF-MS: 432.99 ([M + Na]+). Anal. found: C, 81.95; H, 6.37. C28H26O3 requires C, 81.92; H, 6.38%
In conclusion, we have developed a very simple and highly efficient solvent-free protocol for the synthesis of symmetrical bis(benzhydryl)ethers using inexpensive p-toluenesulfonyl chloride as reagent. The significant features of this environmentally benign and cost-effective straightforward protocol for direct conversion of benzhydrols into symmetrical bis(benzhydryl)ethers include operational simplicity, low reagent loading, high product yields, short reaction time, and solvent-free conditions.
aThe molecular structure of the product, bis(bis- phenylmethyl)ether (1), was determined by means of X-ray crystallographic studies. CCDC 840259 (1) contains the supplementary crystallographic data for this article. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
The authors are thankful to I.I.C.B., Kolkata and Chemistry Department, Kalyani University, India for the spectral measurements. B.B. is grateful to the UGC, New Delhi for awarding him a Senior Research Fellowship. G.B. is thankful to the CSIR, New Delhi for financial support (No. 02(0110)/12/EMR-II dated 01.11.2012). The authors are grateful to Dr. Vivek K. Gupta, Post-Graduate Department of Physics, University of Jammu, Jammu Tawi 180 006, India for collecting the X-ray data.
This study was conducted in memory of Santosh Kr. Brahmachari.
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