- Original article
- Open Access
Facile synthesis of symmetrical bis(benzhydryl)ethers using p-toluenesulfonyl chloride under solvent-free conditions
Organic and Medicinal Chemistry Letters volume 3, Article number: 1 (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.
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.
In continuation of our effort to develop green and solvent-free synthetic methodologies for organic transformations [22–28], we wish to report in this communication a convenient and straightforward protocol for the efficient synthesis of symmetrical bis(benzhydryl)ethers in excellent yields using a catalytic amount of p-toluenesulfonyl chloride under solvent-free conditions (Scheme 1). The process is very simple, cost-effective, and environmentally benign.
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
Firstly, we carried out the synthesis of bis(benzhydryl)ether 1 from benzhydrol as our model reaction in order to optimize the best suited reaction conditions (Figure 1); it was observed (Table 1) that the alcohol in the presence of p-TsCl (5 mol%) afforded the best result with 86% isolated yield at 110°C within a short period of time (15 min) under solvent-free conditions.
A number of benzhydrol derivatives containing mono- and di-chloro, mono-bromo, di-fluoro, mono-methoxy, and mono-methyl phenyl groups were then screened for studying the generality as well as the efficacy of this present procedure (Figure 2; Table 2). All the entries find an easy and efficient route to their symmetrical bis(benzhydryl)ether derivatives in the presence of p-TsCl under solvent-free conditions (Figure 2) within 8 to 15 min affording excellent yields (85% to 92%). The workup of the reaction mixtures is simple and highly convenient. Each product has been characterized by detailed spectral analyses including FT-IR, 1H NMR, 13C NMR, and TOF-MS. In addition, the molecular structure of bis(bis- phenylmethyl)ether (Table 2, entry 1) has unambiguously been confirmed from X-ray crystallographic analysis [29–33] (Figure 3).a
We propose the following mechanistic pathway for the reaction (Scheme 2). p-TsCl reacts rapidly with an equivalent amount of diarylmethanol to generate HCl (and a tosylate derivative as side product) in situ that eventually catalyzes the etherification following a catalytic cycle. The corresponding tosylate derivative remains intact as side product. To ensure the fact, we have checked the reaction with 50 and 100 mol% p-TsCl in two separate entries (entries 13 and 14; Table 1) where benzhydryl p-toluenesulfonate was isolated as 47% and 91% yields, respectively. In addition, we have carried out the reaction with benzhydrol separately using dry HCl gas (passed for a while into the reaction vessel) and concentrated hydrochloric acid; it has been found that dry HCl could also act as an efficient catalyst producing the corresponding ether derivative 1 with 82% yield in 30 min at 110°C, while concentrated HCl (45 mg added to 1 mmol of benzhydrol) required much more time (45 min) producing less amount of yield (62%) at the same reaction temperature. These experimental observations support our proposed mechanistic pathway as well.
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.
Brahmachari G: Handbook of pharmaceutical natural products. 1st edition. Weinheim: Wiley-VCH; 2010.
Li X, Upton TG, Gibb CLD, Gibb BC: Resorcinarenes as templates: a general strategy for the synthesis of large macrocycles. J Am Chem Soc 2003, 125: 650–651. 10.1021/ja029116g
Ley SV, Thomas AW: Modern synthetic methods for copper-mediated C(aryl)-O, C(aryl)-N, and C(aryl)-S bond formation. Angew Chem Int Ed 2003, 42: 5400–5449. 10.1002/anie.200300594
Tlili A, Monnier F, Taillefer M: Selective one-pot access to symmetrical or unsymmetrical diaryl ethers by copper-catalyzed double arylation of a simple oxygen source. Chem Eur J 2010, 16: 12299–12302. 10.1002/chem.201001373
Tan ES, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS: Exploring the structure-activity relationship of the ethylamine portion of 3-iodothyronamine for rat and mouse trace amine-associated receptor 1. J Med Chem 2007, 50: 2787–2798. 10.1021/jm0700417
Nicolaou KC, Boddy CNC, Brase S, Winssinger N: Chemistry, biology and medicine of the glycopeptide antibiotics. Angew Chem Int Ed 1999, 38: 2097–2152.
Harris CM, Kopecka H, Harris TM: Vancomycin: structure and transformation to CDP-I. J Am Chem Soc 1983, 105: 6915–6922. 10.1021/ja00361a029
Barna JCJ, Williams DH, Stone DJM, Leung TWC, Doddrell DM: Structure elucidation of the teicoplanin antibiotics. J Am Chem Soc 1984, 106: 4895–4902. 10.1021/ja00329a044
Hayashi M: Drug Data Report 704 (JP 97077745). Barcelona: J. R. Prous Science; 1997.
Su D, Lim JJ, Tinney E, Wan B, Young MB, Anderson KD, Rudd D, Munshi V, Bahnck C, Felock PJ, Lu M, Lai M, Touch S, Moyer G, DiStefano DJ, Flynn JA, Liang Y, Sanchez R, Perlow-Poehnelt R, Miller M, Vacca JP, Williams TM, Anthony NJ: Biaryl ethers as novel non-nucleoside reverse transcriptase inhibitors with improved potency against key mutant viruses. J Med Chem 2009, 52: 7163–7169. 10.1021/jm901230r
Weis R, Schlapper C, Brun CR, Kaiser M, Seebacher W: Antiplasmodial and antitrypanosomal activity of new esters and ethers of 4-dialkylaminobicyclo[2.2.2]octan-2-ols. Eur J Pharm Sci 2006, 28: 361–368. 10.1016/j.ejps.2006.04.003
Van Der Zee P, Hespe W: A comparison of the inhibitory effects of aromatic substituted benzhydryl ethers on the uptake of catecholamines and serotonin into synaptosomal preparations of the rat brain. Neuropharmacol 1978, 17: 483–490. 10.1016/0028-3908(78)90054-0
Nilsson JL, Wågermark J, Dahlbom R: Potential antiparkinsonism agents. Quinuclidinyl benzhydryl ethers. J Med Chem 1969, 12: 1103–1105. 10.1021/jm00306a034
McGavack TH, Schulman PM, Boyd LJ: A clinical investigation of beta-morpholino-ethyl benzhydryl ether hydrochloride (linadryl) as an antihistamine agent. J Allergy 1948, 19: 141–145. 10.1016/0021-8707(48)90102-6
Loew ER, Kaiser ME: Alleviation of anaphylactic shock in guinea pigs with synthetic benzhydryl alkamine ethers. Exp Biol Med 1945, 58: 235–237.
Pyo MK, Jin JL, Koo YK, Yun-Choi S: Phenolic and furan type compounds isolated from Gastrodia elata and their anti-platelet effects. Arch Pharm Res 2004, 27: 381–385. 10.1007/BF02980077
Pitsinos EN, Vidali VP, Couladouros EA: Diaryl ether formation in the synthesis of natural products. Eur J Org Chem 2011, 7: 1207–1222.
Pratt EF, Draper JD: Reaction rates by distillation. I. The etherification of phenylcarbinols and the transetherification of their ethers1. J Am Chem Soc 1949, 71: 2846–2849. 10.1021/ja01176a075
Welch CM, Smith HA: The properties of benzhydrol in sulfuric acid solution. J Am Chem Soc 1950, 72: 4748–4750. 10.1021/ja01166a112
Smith HA, Thompson RG: Preparation and properties of substituted benzhydryl carbonium ions. J Am Chem Soc 1955, 77: 1778–1783. 10.1021/ja01612a018
Toda F, Takumi H, Akehi M: Efficient solid-state reactions of alcohols: dehydration, rearrangement, and substitution. J Chem Soc Chem Commun 1990, 1270–1271.
Brahmachari G, Laskar S: A very simple and highly efficient procedure for N -formylation of primary and secondary amines at room temperature under solvent-free conditions. Tetrahedron Lett 2010, 51: 2319–2322. 10.1016/j.tetlet.2010.02.119
Brahmachari G, Laskar S, Sarkar S: Metal acetate/metal oxide in acetic acid: an efficient reagent for the chemoselective N -acetylation of amines. J Chem Res 2010, 34: 288–295.
Brahmachari G, Laskar S, Sarkar S: A green approach to chemoselective N -acetylation of amines using catalytic amount of zinc acetate in acetic acid under microwave irradiation. Indian J Chem 2010, 49B: 1274–1281.
Brahmachari G, Das S: Bismuth nitrate-catalyzed multicomponent reaction for efficient and one-pot synthesis of densely functionalized piperidine scaffolds at room temperature. Tetrahedron Lett 2012, 53: 1479–1484. 10.1016/j.tetlet.2012.01.042
Brahmachari G, Banerjee B: A comparison between catalyst-free and ZrOCl 2 ·8H 2 O-catalyzed Strecker reactions for the rapid and solvent-free one-pot synthesis of racemic α-aminonitrile derivatives. Asian J Org Chem 2012, 1: 251–258.
Brahmachari G, Das S: One-pot synthesis of 3-[( N -alkylanilino)(aryl)methyl] indoles via a transition metal assisted three-component condensation at room temperature. J Het Chem 2013. in press
Brahmachari G, Das S: A simple and straightforward method for one-pot synthesis of 2,4,5-triarylimidazoles using titanium dioxide as an eco-friendly and recyclable catalyst under solvent-free conditions. Indian J Chem Sec B 2013, 52B: 387–393.
Sheldrick GM: SHELXS97, Program for the solution of crystal structures. Gottingen: University of Gottingen; 1997.
Farrugia LJ: ORTEP-3 for windows—a version of ORTEP-III with a graphical user interface (GUI). J Appl Cryst 1997, 30: 565–566.
Farrugia LJ: WinGX suite for small-molecule single-crystal crystallography. J Appl Cryst 1999, 32: 837–838. 10.1107/S0021889899006020
Nardelli M: PARST95-An update to PARST. A system of Fortran routines for calculating molecular structure parameters from the results of the crystal structure analysis. J Appl Cryst 1995, 28: 659. 10.1107/S0021889895007138
Spek AL: Structure validation in chemical crystallography. Acta Cryst 2009, D65: 148–155.
Koloves M, Froussios C: O -diphenylmethylation of alcohols and carboxylic acids using diphenylmethyl diphenyl phosphate as alkylating agent. Tetrahedron Lett 1984, 25: 3909–3912. 10.1016/S0040-4039(01)91201-8
Grummitt O, Buck AC: Di-(p, p′-dichlorobenzohydryl) ether. J Am Chem Soc 1945, 67: 693.
Welch CM, Smith HA: Reactions of carboxylic acids in sulfuric acid. J Am Chem Soc 1953, 75: 1412–1415. 10.1021/ja01102a042
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.
The authors declare that they have no competing interests.