Iron-Catalyzed Selective Etherification and Transetherification Reactions Using Alcohols.

Simple and readily available iron(III) triflate turned out to be a cheap, environmentally benign, and efficient catalyst for the direct etherification of alcohols. The use of ammonium chloride as an additive (5 mol %, 1 equiv relative to catalyst) suppressed the side reactions completely and ensured the selective ether formation even on challenging substrates containing electron-donating substituents. This method allows the selective synthesis of symmetrical ethers from benzylic secondary alcohols and unsymmetrical ethers directly from secondary and primary alcohols. Moreover, transetherification of symmetrical ethers using primary alcohols is attained. The reaction progress of symmetrical ether and unsymmetrical ether formation followed zero-order and first-order kinetics, respectively. Electron paramagnetic resonance (EPR) measurements of the reaction mixture and simple iron(III) triflate clearly indicated that oxidation state of the metal center remains same throughout the catalysis. Mechanistic studies confirmed that the unsymmetrical ether formation occurs via the in situ formed symmetrical ethers.

Introduction

Ethers have widespread applications as solvents, plasticizers, disinfectants, herbicides, drug intermediates, fragrances, and precursors for polymers.[1] Etherification is an important transformation in organic synthesis, which traditionally employs sodium alkoxide and alkyl halides as originally devised by Williamson (Scheme a).[2] Although this method is particularly useful for the preparation of unsymmetrical ethers, it suffers from drawbacks such as generation of stoichiometric amount of inorganic waste and requirement of alkyl halides, which are derived from alcohols, making the ether synthesis an ultimate multistep process.[3] Transition-metal-catalyzed methods are developed for the synthesis of ethers from diverse functional groups to circumvent these shortcomings. For example, aryl-substituted ethers are derived from aryl halides and alcohols using Pd- and Cu-catalyzed Ullmann-type synthesis.[4] Mitsunobu-type etherification reactions,[5] reductive deoxygenation of esters,[6] oxidation–reduction condensation of alcohols via alkoxydiphenylphosphines,[7] hydroetherification of alkenes using alcohols,[8] and oxidative etherification of aryl C–H bonds are reported.[9] However, these methods have limited scope and also suffer from poor atom economy.

Scheme 1

Synthesis of Ethers: Catalytic vs Conventional Methods

Direct coupling of alcohols to ether is attractive as it offers the atom economical and environmentally benign method with eliminated water as the only byproduct (Scheme b).[10] However, due to poor ability of the hydroxyl functionality as a leaving group, hydroxide activation is challenging, particularly for the nucleophilic substitution, which is recognized as an important topic in green chemistry.[11] Thus, dehydration of alcohols developed for the ether synthesis became an important transformation in organic synthesis with widespread use.[12] Ethers are produced in large scale using heterogeneous acid or strong Brønsted acid catalysts.[13] Efficient synthesis of unsymmetrical ethers directly from two different alcohols is also achieved using transition-metal catalysts (Scheme b).[14] Recently, a radical pathway for the dehydrative O-alkylation reaction between alcohols has been reported, albeit at elevated temperature.[15] Iron is an earth abundant, less toxic, and environmentally benign metal that can potentially provide economical advantage and poised to emulate the catalytic activities of noble metals.[16] Iron-catalyzed dehydrative etherification is scarcely investigated in the literature with limited substrate scopes.[17] Thus, development of a simple, readily available iron catalyst that can catalyze the selective formation of both symmetrical and unsymmetrical ethers directly from alcohols is a desired goal.

Herein, we report a highly selective dehydrative formation of symmetrical and unsymmetrical ethers of two different alcohols. This catalytic method can tolerate wide range of functional groups by generating water as a sole byproduct under mild conditions. These reactions proceed via activation of secondary benzylic alcohols to form symmetrical ethers and subsequently unsymmetrical ethers formed in the presence of primary alcohols.

Results and Discussion

At the outset of our studies, we focused our attention to optimize the reaction conditions for the synthesis of symmetrical ethers. Thus, 1-phenylethanol was reacted with iron(III) salts in different solvents. When FeCl3·6H2O (5 mol %) was reacted with 1-phenylethanol in dichloromethane (DCM) at 0 °C, oxybis(ethane-1,1-diyl)dibenzene (1a) formed in 65% yield together with an alkene side product 2 in 15% yield (entry 1, Table ). Further, Fe(NO3)3 was screened under similar reaction conditions, which did not provide the desired product (entry 2, Table ).[17f] Upon employing Fe(OTf)3 as a catalyst, the desired ether product was obtained in only 10%, whereas the formation of alkene was observed in 70% yield (entry 3, Table ). Perhaps, the enhanced acidity in the reaction medium due to the use of iron(III) triflate resulted in promoting the formation of alkene side product, which we envisaged to suppress by the use of ammonium salts as an additive. Direct catalytic etherification of 1-phenylethanol was performed with Fe(OTf)3 (5 mol %) and NH4Cl (5 mol %, 1 equiv relative to catalyst) to obtain the desired oxybis(ethane-1,1-diyl)dibenzene (1a) in 81% yield (entry 4, Table ). Gratifyingly, no formation of the alkene side product was observed. Further increase of NH4Cl load to 20 mol % made almost no impact on catalysis (entry 5, Table ). Notably, the direct etherification of alcohols catalyzed by iron(III) triflate is very sensitive to the solvent medium. When other polar solvents (such as acetonitrile, tetrahydrofuran (THF), and acetone, entries 6–8, Table ) and nonpolar solvents like toluene (entry 9, Table ) were used, no reaction occurred. Further, control experiments in dichloromethane without catalyst or only with NH4Cl provided no product, clearly indicating that direct ether formation from alcohols is essentially a catalytic process (entries 10 and 11, Table ). Remarkably, the reaction conditions are very simple and require no inert atmosphere.

Table 1

Synthesis of Symmetrical Ethers: Optimization of Reaction Conditionsa

entry	catalyst (mol %)	solvent	yield of 1a/2 (%)b
1	FeCl3·6H2O (5)	DCM	65/15
2	Fe(NO3)3 (5)	DCM	0
3	Fe(OTf)3 (5)	DCM	10/70
4	Fe(OTf)3 (5) + NH4Cl (5)	DCM	81/0
5	Fe(OTf)3 (5) + NH4Cl (20)	DCM	80/0
6	Fe(OTf)3 (5) + NH4Cl (5)	CH3CN	trace
7	Fe(OTf)3 (5) + NH4Cl (5)	THF	0
8	Fe(OTf)3 (5) + NH4Cl (5)	acetone	0
9	Fe(OTf)3 (5) + NH4Cl (5)	toluene	0
10		DCM	0
11	NH4Cl (5)	DCM	0

Reaction conditions: 1-phenylethanol (0.5 mmol), solvent (2 mL), Fe(OTf)3 (0.025 mmol, 5 mol %), and NH4Cl (0.025 mmol, 5 mol %) were stirred at 0 °C to room temperature (rt) for 0.5 h in open air.

Isolated yield.

Using the optimized conditions, an assortment of 1-substituted secondary benzyl alcohols was subjected to iron(III) triflate-catalyzed direct etherification reactions. 1-Phenylpropanol provided the corresponding product in 67% yield (entry 2, Table ). However, alcohols having electron-donating substituents on the aryl ring displayed enhanced reactivity and the corresponding products 1c–f were isolated in very good yields (87–93%, entries 3–6, Table ). Although all of these reactions completed in 30 min, the secondary benzyl alcohols having electron-withdrawing fluorine substituent required prolonged reaction time (3 h) to provide the product 1g in 81% yield (entry 7, Table ). The catalyst was also effective in promoting the reaction of 1,2,3,4-tetrahydro-1-naphthol, and the corresponding ether 1h was obtained in 65% yield (entry 8, Table ). When the sterically more demanding diphenylmethanol and bromo diphenylmethanol were subjected to catalysis, the corresponding symmetrical ethers 1i and 1j were isolated in 82 and 91% yields, respectively (entries 9 and 10, Table ). Representatively, a single-crystal X-ray structure of diphenylmethyl ether 1i was solved,[18] which clearly established ether formation from the dehydrative coupling of diphenylmethanol.

Table 2

Iron(III)-Catalyzed Symmetrical Etherification of Substituted Benzylic Alcohola

Reaction conditions: 1-phenylethanol derivatives (0.5 mmol), DCM (2 mL), Fe(OTf)3 (0.025 mmol, 5 mol %), and NH4Cl (0.025 mmol, 5 mol %) were stirred at 0 °C to rt in open air.

Isolated yield.

Next, we investigated the formation of unsymmetrical ethers using two different alcohols (Table ). When 1-phenylethanol was reacted with 1-propanol in the presence of iron(III) triflate (5 mol %), ammonium chloride (5 mol %) at 0 °C to room temperature incomplete reaction was observed and the reaction mixture contains both symmetrical and unsymmetrical ether products. Thus, upon carrying out the similar experiment of direct catalytic etherification at 45 °C, the unsymmetrical ether 3a was obtained in 88% yield after 12 h. Further to verify the efficiency of Fe(NO3)3·9H2O, catalytic reaction was performed under optimized condition, which resulted in no formation of unsymmetrical ether 3a.[17f] Secondary alcohols like 1-substituted benzyl alcohols containing electron-donating substituents on the aryl ring were reacted with linear primary alcohols. All of these reactions completed within 2–12 h, and the unsymmetrical ethers 3a–g were isolated in good yields. The unsymmetrical ether formation was sensitive to the steric hindrance on the secondary alcohols. Thus, reaction of 1-mesitylethanol with 1-pentanol provided the corresponding unsymmetrical ether 3h in 45% yield. Notably, when 1-(4-chlorophenyl)ethanol was reacted with methanol, the reaction completed in 10 h to provide the unsymmetrical ether 3i in 91% yield. Further, primary benzyl alcohols were reacted with secondary benzyl alcohols; reaction of 1-(p-tolyl)ethanol with benzyl alcohol and 4-methyl benzyl alcohol provided the corresponding unsymmetrical ethers 3j and 3k in excellent yields. However, upon employing the primary benzyl alcohols containing electron-withdrawing groups, reactions occurred for more than 24 h (3l–n) and the 4-nitrobenzyl alcohol provided the product 3n only in 45% yield. Gratifyingly, reaction of 1-(p-tolyl)ethanol with hept-2-yn-1-ol delivered the ether product in excellent yield 3p of 95%, without generating any side product under this mild experimental condition. Reaction of 1-(4-methoxyphenyl)ethanol with tetrahydrofurfural provided only 40% product 3q. Interestingly, tertiary alcohol also underwent unsymmetrical etherification with nonbenzylic aliphatic primary alcohol. Reaction of tert-butanol and 3-phenylpropanol provided 40% 3r upon heating at 70 °C.

Table 3

Iron(III)-Catalyzed Unsymmetrical Etherification of Two Different Alcoholsa

Reaction conditions: secondary alcohol (0.5 mmol), primary alcohol (0.5 mmol), Fe(OTf)3 (0.025 mmol, 5 mol %), and NH4Cl (0.025 mmol, 5 mol %) in DCM (2 mL) were heated at 45 °C for indicated time.

Fe(NO3)3·9H2O (0.025 mmol, 5 mol %) was used as catalyst.

Reaction was carried out at 70 °C. Reported yields correspond to isolated product after column chromatographic purification.

Next, we investigated the formation of unsymmetrical ethers using symmetrical ethers and alcohols (Table ). As the unsymmetrical ethers are more thermodynamically stable than the symmetrical ethers, the reverse formation of symmetrical ethers does not occur. All of these transetherification reactions completed within 1–12 h, and the unsymmetrical ethers 3b and 4a–f were isolated in good yields. Gratifyingly, reactions tolerate alkene and alkyne functionalities. (Oxybis(ethane-1,1-diyl))dibenzene (1a) was reacted with 1-pentanol, but-3-en-1-ol, hex-3-yn-1-ol, and (2-fluorophenyl)methanol in the presence of iron(III) triflate (5 mol %) and ammonium chloride (5 mol %) at room temperature, which provided the corresponding unsymmetrical ethers 3b, 4a–c, respectively, in very good yields. Further, the unsymmetrical ethers 4d–f were also obtained from transetherification of (oxybis(methanetriyl))tetrabenzene (1i) with but-3-en-1-ol, 2-ethylbutan-1-ol, and 3-methoxybutan-1-ol, respectively.

Table 4

Iron(III)-Catalyzed Transetherification of Symmetrical Ethers with Alcoholsa

Reaction conditions: symmetrical ether (0.5 mmol), primary alcohol (1 mmol), DCM (2 mL), Fe(OTf)3 (0.025 mmol, 5 mol %), and NH4Cl (0.025 mmol, 5 mol %) were stirred at rt in open air.

The mechanistic insights for the iron(III)-catalyzed direct etherification of alcohols are deciphered by performing elementary reactions and in situ analysis of the reaction progress. 1-(p-Tolyl)ethanol was reacted with 1-pentanol for 2 h at three different temperatures; at 0 °C, no formation of unsymmetrical ether 3f was observed, whereas reactions performed at room temperature and 35 °C provided 3f in 75 and 80% yields (Scheme a). Moreover, the reaction progress of the symmetrical and unsymmetrical etherification processes was monitored using the gas chromatography (GC) to study the kinetics. The reaction progress for self-etherification of 1-(p-tolyl)ethanol catalyzed by Fe(OTf)3/NH4Cl followed a linear line, indicating a zero-order kinetics (Figure a). When the reaction progress for cross-etherification of 1-(p-tolyl)ethanol with 1-pentanol was monitored by GC (which followed first-order kinetics), the formation and disappearance of the symmetrical ether (1c) intermediate, concomitantly transforming to the ultimate unsymmetrical ether product 3f, was observed in the reaction mixture (Figure b). These observations confirm that the formation of unsymmetrical ether goes via in situ formed symmetrical ether and subsequent nucleophilic attack by a primary alcohol. To study the chemoselectivity and electronic influence of primary alcohols on the unsymmetrical ether formation, an equimolar mixture of 4-methylbenzyl alcohol and 4-cyanobenzyl alcohol was reacted with 1-(p-tolyl)ethanol to afford 3k and 3o in a ratio of 1.15:1, respectively. This observation indicates that the electron-rich benzylic alcohol is slightly more reactive than the electron-deficient primary alcohols (Scheme b). To confirm the role of ammonium chloride, further experiment with tetraethyl ammonium chloride under similar reaction condition was performed and no conversion of 1-phenylethanol was noted, which ruled out the possible involvement of Cl– counter anion in catalytic cycle. Therefore, active participation of NH4+ ion in the catalytic cycle is anticipated (Scheme c). Moreover, to investigate the reversibility from symmetrical ether to alcohol, reaction was performed with two different symmetrical ethers under similar reaction condition. Reaction of (oxybis(ethane-1,1-diyl))dibenzene (1a) with (oxybis(methanetriyl))tetrabenzene (1i) in the presence of iron(III) triflate (5 mol %) and ammonium chloride (5 mol %) at room temperature provided the corresponding alkene 5 in 71% yield (Scheme d). However, in this case, reaction did not stop at the formation of unsymmetrical ether and proceeded to the formation of corresponding alkene 5. These studies indicate reversibility between intermediates I and II during the progress of the reaction. Further, 1-phenylethanol was reacted with 1-pentanol in the presence of Fe(OTf)3 (5 mol %), ammonium chloride (5 mol %), and molecular sieves (3 Å) at 45 °C for 12 h, which provided 75% conversion of 1-phenylethanol and 55% unsymmetrical ether (Scheme e).

Scheme 2

Mechanistic Studies for the Catalytic Etherification and Transetherification

Figure 1

In situ monitoring of the reaction progress for the (a) symmetrical and (b) unsymmetrical ether formation.

Electron paramagnetic resonance (EPR) measurements were carried out at room temperature (298 K) in dichloromethane to investigate the change in oxidation state of iron(III) triflate during the course of reaction. The EPR measurements of the reaction mixture (3a, Table ) were carried out at room temperature for the reaction of 1-phenylethanol and 1-propanol. The reaction mixture was monitored from 0 to 40 min at regular interval to observe the catalytically active species for the etherification of alcohol (Figure S74). The corresponding g value (g = 2.016) of the reaction mixture is almost similar to that of iron(III) triflate in dichloromethane (g = 2.013), which clearly indicates that the oxidation state of the metal center remains same during catalysis. Moreover, EPR graph of the reaction mixture shows fine structure (Figure ), which indicates spin value S = 5/2 (d5, high spin) attributing to iron(III) species. However, the width between corresponding extreme slopes of reaction mixture (at 40 min) and iron(III) triflate EPR signals are 45G and 224G, respectively. This difference between line width of EPR signals is perhaps due to change in the chemical environment around the metal center during the reaction progress.

Figure 2

X-band electron paramagnetic resonance (EPR) spectra of Fe(OTf)3 (black line) and reaction mixture of 1-phenyl ethanol, 1-propanol, ammonium chloride, and Fe(OTf)3 (red line). Spectra were recorded at room temperature in DCM solution under microwave frequency (9.85 GHz).

On the basis of these experimental observations, the mechanism of the iron(III)-catalyzed dehydrative etherification of alcohols was proposed as described in Scheme . The reaction of iron(III) catalyst with secondary benzylic alcohols leads to the formation of zwitterionic intermediate I. Upon reaction with another molecule of secondary alcohol via dehydration (self-condensation), intermediate I is transformed to II. This reaction involves the C–O bond cleavage and in situ formation of benzylic carbocation. The stability of benzylic carbocation is well documented in the literature and has been the subject of theoretical and experimental studies.[17g] At low temperature, the symmetrical ether dissociates from the intermediate II to regenerate the catalyst. In the presence of primary alcohols in the reaction mixture, a second intermolecular nucleophilic attack by primary alcohol occurs at slightly elevated temperature (45 °C), leading to the formation of unsymmetrical ether product and intermediate I. The selective formation of unsymmetrical ether product from the symmetrical ether is due to the reversible formation of intermediate II from the symmetrical ethers and higher nucleophilicity of primary alcohols over the secondary alcohols.

Scheme 3

Proposed Mechanism for the Direct Catalytic Etherification of Alcohols

Conclusions

In summary, we have developed an efficient method for the selective synthesis of symmetrical and unsymmetrical benzylic ethers from different alcohols using Fe(OTf)3 and ammonium chloride. The use of ammonium chloride as an additive completely suppressed the side reactions and ensured the selective formation of ethers. As these reactions proceeded under mild experimental conditions and in open air, a variety of functional groups are well tolerated. An assortment of symmetrical and unsymmetrical ether derivatives was synthesized by dehydration of benzylic alcohols. Remarkably, by transetherification, unsymmetrical ethers were also synthesized using symmetrical ethers and alcohols in very good yields. Mechanistic studies clearly indicated that oxidation state of the catalyst remains same throughout the catalysis and that the formation of unsymmetrical ethers occurs from the in situ formed symmetrical ethers. The use of ligand-free, simple, cheap, and readily available iron(III) triflate as a catalyst makes this protocol highly attractive and environmentally benign.

Experimental Section

General Experimental Procedure

All catalytic reactions were performed under open atmosphere. Iron catalyst was purchased from Sigma-Aldrich. Dry solvents were prepared according to standard procedures. 1H and 13C spectra were recorded at 400 MHz (1H: 400 MHz, 13C: 100.6 MHz) and 700 MHz (1H: 700 MHz, 13C: 176 MHz) NMR. 1H and 13C {1H} NMR chemical shifts were reported in ppm downfield from tetramethyl silane. Multiplicity is abbreviated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; m, multiplate. IR spectra were recorded on an Fourier transform infrared spectrometer. Mass spectra were recorded on a micrOTOF-Q II spectrometer. EPR spectra were recorded on a QCW–EPR bridge X band spectrometer.

GC Method

Gas chromatography analyses were performed using a gas chromatograph equipped with a SH-Rtx-1 capillary column (30 m × 250 μm). The instrument was set to an injection volume of 1 μL, an inlet split ratio of 100:1, and inlet and detector temperatures of 250 and 280 °C, respectively. Ultrahigh purity-grade nitrogen was used as carrier gas with a flow rate of 120.9 mL/min. The temperature program used for all of the analyses is as follows: 50 °C, 1 min; 12 °C/min to 250 °C, 10 min. Response factor for all of the necessary compounds with respect to standard n-dodecane was calculated from the average of three independent GC runs.

General Procedure for the Synthesis of Symmetrical Ether

Benzyl alcohol (0.5 mmol), ammonium chloride (1.3 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a round-bottom flask with a stirrer bar under open atmosphere. The reaction mixture was stirred at 0 °C and allowed to warm at room temperature. After completion of the reaction (monitored by thin layer chromatography (TLC) and GC), analytically pure product was isolated by column chromatography on silica gel (100–200 mesh, petroleum ether/EtOAc = 100:0–10:1).

Spectral Data of Symmetrical Ethers (Oxybis(ethane-1,1-diyl))dibenzene)[19] (1a)

Mixture of two diastereoisomers, ca. 1:1. Yield 45 mg, 81%. Yellow liquid. IR (DCM): 2972, 2854, 1947, 1602, 1450, 1368, 1204, 1090, 1029, 761, 699 cm–1. For first isomer 1H NMR (CDCl3): δ 7.13–7.30 (m, 10H), 4.17 (q, 1H, J = 6.4 Hz), 1.31 (d, 3H, J = 6.4 Hz); for second isomer 1H NMR (CDCl3): δ 7.13–7.30 (m, 10H), 4.46 (q, 1H, J = 6.4 Hz), 1.39 (d, 3H, J = 6.4 Hz). 13C {1H} NMR (CDCl3): δ 144.4, 144.3, 128.6, 128.4, 127.5, 127.3, 126.4, 126.3, 74.7, 74.5, 24.8, 23.1.

(E)-But-1-ene-1,3-diyldibenzene[20] (2)

Yield 36 mg, 70%. Yellow liquid. IR (DCM): 3026, 2965, 1647, 1493, 1450, 1373, 965, 743, 540 cm–1. 1H NMR (CDCl3): δ 7.09–7.29 (m, 10H), 6.27–6.36 (m, 2H), 3.53–3.59 (m, 1H), 1.39 (d, 3H, J = 7.2 Hz). 13C {1H} NMR (CDCl3): δ 145.8, 137.7, 135.4, 128.7, 128.6, 127.4, 127.2, 126.4, 126.3, 42.7, 21.4.

(Oxybis(propane-1,1-diyl))dibenzene[21] (1b)

Mixture of two diastereoisomers, ca. 1:1.74. Yield 42 mg, 67%. Colorless liquid. IR (DCM): 2974, 2882, 1597, 1490, 1369, 1203, 1089, 827, 782, 538 cm–1. For major isomer 1H NMR (CDCl3): δ 7.09–7.29 (m, 10H), 3.88 (t, 1H, J = 6.8 Hz), 1.63–1.84 (m, 2H), 0.72 (t, 3H, J = 7.6 Hz); for minor isomer 1H NMR (CDCl3): δ 7.09–7.29 (m, 10H), 4.21 (t, 1H, J = 6.4 Hz), 1.52–1.58 (m, 2H), 0.79 (t, 3H, J = 7.2 Hz). 13C {1H} NMR (CDCl3): δ 142.7, 142.5, 133.3, 133.0, 128.9, 128.6, 127.8, 127.7, 74.9, 74.3, 24.7, 23.2.

4,4′-(Oxybis(ethane-1,1-diyl))bis(methylbenzene)[14d] (1c)

Mixture of two diastereoisomers, ca. 1:3. Yield 59 mg, 93%. Colorless liquid. IR (DCM): 2972, 2866, 1902, 1613, 1513, 1445, 1367, 1203, 1092, 816, 720, 542 cm–1. For major isomer 1H NMR (CDCl3): δ 7.01–7.11 (m, 8H), 4.13 (q, 1H, J = 6.4 Hz), 2.28 (s, 3H), 1.28 (d, 3H, J = 6.4 Hz); for minor isomer 1H NMR (CDCl3): δ 7.01–7.11 (m, 8H), 4.42 (q, 1H, J = 6.4 Hz), 2.24 (s, 3H), 1.36 (d, 3H, J = 6.4 Hz). 13C {1H} NMR (CDCl3): δ 141.4, 141.3, 137.1, 136.8, 129.3, 129.1, 126.4, 126.3, 74.4, 74.0, 24.8, 23.0, 21.3, 21.2.

2,2′-(Oxybis(ethane-1,1-diyl))bis(methylbenzene)) (1d)

Mixture of two diastereoisomers, ca. 1:2. Yield 57 mg, 92%. Colorless liquid. IR (DCM): 2972, 2866, 1902, 1613, 1513, 1445, 1367, 1203, 1092, 816, 720, 542 cm–1. For major isomer 1H NMR (CDCl3): δ 6.98–7.42 (m, 8H), 4.37 (q, 1H, J = 6.3 Hz), 1.95 (s, 3H), 1.28 (d, 3H, J = 6.3 Hz); for minor isomer 1H NMR (CDCl3): δ 6.98–7.42 (m, 8H), 4.65 (q, 1H, J = 6.3 Hz), 2.09 (s, 3H), 1.33 (d, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 142.7, 142.3, 135.2, 134.3, 130.4, 130.2, 127.1, 126.8, 126.5, 126.3, 126.0, 125.9, 71.11, 71.06, 23.5, 22.4, 19.1, 18.8. High-resolution mass spectrometry (HRMS) (electrospray ionization (ESI)) m/z: [M + Na]+ calcd for C18H22ONa, 277.1562; found 277.1582.

2,2′-(Oxybis(ethane-1,1-diyl))bis(1,3,5-trimethylbenzene) (1e)

Yield 72 mg, 93%. Yellow solid. mp 119–120 °C. IR (DCM): 2915, 2051, 1602, 1443, 1218, 1087, 1033, 848 cm–1. 1H NMR (CDCl3): δ 5.84–6.19 (m, 4H), 4.066 (m, 2H), 2.16 (d, 18H, J = 5.6 Hz), 1.43 (dd, 6H, J = 6.4 Hz). 13C {1H} NMR (CDCl3): δ 139.0, 138.7, 136.5, 135.9, 135.7, 135.4, 134.7, 128.6, 125.7, 37.3, 21.4, 21.0, 20.8, 18.2. HRMS (ESI) m/z: [M + Na]+ calcd for C22H30ONa, 333.2189; found 333.2162.

4,4′-(Oxybis(ethane-1,1-diyl))bis(chlorobenzene) (1f)

Mixture of two diastereoisomers, ca. 1:1.10. Yield 68 mg, 93%. Light yellow liquid. IR (DCM): 2961, 2873, 1454, 1356, 1260, 1082, 1055, 801, 755, 700 cm–1. For major isomer 1H NMR (CDCl3): δ 7.09–7.26 (m, 8H), 4.10 (q, 1H, J = 6.4 Hz), 1.27 (d, 3H, J = 6.8 Hz); for minor isomer 1H NMR (CDCl3): δ 7.09–7.26 (m, 8H), 4.39 (q, 1H, J = 6.4 Hz), 1.35 (d, 3H, J = 6.8 Hz). 13C {1H} NMR (CDCl3): δ 143.1, 143.0, 128.4, 128.0, 127.5, 127.3, 127.0, 126.9, 80.7, 80.1, 31.5, 29.8. HRMS (ESI) m/z: [M + Na]+ calcd for C16H16Cl2ONa, 317.0470; found 317.0493.

4,4′-(Oxybis(ethane-1,1-diyl))bis(fluorobenzene) (1g)

Mixture of two diastereoisomers, ca. 1:1.25. Yield 53 mg, 81%. Colorless liquid. IR (DCM): 2975, 2889, 1604, 1509, 1444, 1370, 1223, 1089, 1026, 834, 544 cm–1. For major isomer 1H NMR (CDCl3): δ 6.85–7.15 (m, 8H), 4.10 (q, 1H, J = 7 Hz), 1.26 (d, 3H, J = 7 Hz); for minor isomer 1H NMR (CDCl3): δ 6.85–7.15 (m, 8H), 4.39 (q, 1H, J = 6.3 Hz), 1.35 (d, 3H, J = 7 Hz). 13C {1H} NMR (CDCl3): δ 163.0, 162.8, 161.6, 161.4, 139.98, 139.96, 139.74, 139.72, 127.98, 127.94, 127.92, 127.87, 115.5, 115.4, 115.2, 115.1, 74.2, 74.0, 24.8, 23.2. HRMS (ESI) m/z: [M + Na]+ calcd for C16H16F2ONa, 285.1061; found 285.1083.

1-((1,2,3,4-Tetrahydronaphthalen-2-yl)oxy)-1,2,3,4-tetrahydronaphthalene[14d] (1h)

Yield 45 mg, 65%. Colorless liquid. IR (DCM): 2964, 2873, 1458, 1354, 1259, 1093, 708 cm–1. 1H NMR (CDCl3): δ 7.04–7.12 (m, 8H), 3.63 (q, 2H, J = 3.5 Hz), 2.71–2.75 (m, 4H), 2.03–2.15 (m, 4H), 1.64–1.78 (m, 4H). 13C {1H} NMR (CDCl3): δ 145.8, 138.1, 137.8, 135.0, 134.9, 129.4, 129.2, 127.3, 126.6, 126.4, 126.1, 125.8, 125.7, 125.3, 47.4, 30.0, 28.71, 28.69, 25.3, 21.6.

(Oxybis(methanetriyl))tetrabenzene[14d] (1i)

Yield 71 mg, 82%. White solid. mp 109–110 °C. IR (DCM): 3026, 2870, 1493, 1262, 1185, 1085, 1058, 740, 699 cm–1. 1H NMR (CDCl3): δ 7.13–7.30 (m, 20H), 5.32 (s, 2H). 13C {1H} NMR (CDCl3): δ 142.3, 128.5, 127.6, 127.4, 80.1.

4,4′-(Oxybis(phenylmethylene))bis(bromobenzene)[18] (1j)

Yield 114 mg, 91%. Colorless amorphous solid. mp 133–135 °C. IR (DCM): 3028, 2871, 1590, 1484, 1402, 1290, 1185, 1069, 1027, 714, 702, 582 cm–1. 1H NMR (CDCl3): δ 7.12–7.36 (m, 18H), 5.24 (s, 2H). 13C {1H} NMR (CDCl3): δ 141.5, 141.4, 141.2, 141.1, 131.74, 131.67, 129.0, 128.9, 128.7, 128.7, 128.0, 79.7, 79.7.

General Procedure for Synthesis of Unsymmetrical Ether

Using Two Different Alcohols

Benzyl alcohol (0.5 mmol), aliphatic alcohol (0.5 mmol), ammonium chloride (1.3 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a sealed tube with a stirrer bar under open atmosphere. The reaction mixture was stirred at 45 °C for specified time. After completion of the reaction (monitored by TLC and GC), analytically pure product was isolated by a column chromatography on silica gel (100–200 mesh, petroleum ether/EtOAc = 100:0–10:1).

Using Ether and Alcohol

Symmetrical ether (0.5 mmol), primary alcohol (1.0 mmol), ammonium chloride (1.3 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a 20 mL vial with a stirrer bar under open atmosphere. The reaction mixture was stirred at room temperature for specified time. After completion of the reaction (monitored by TLC and GC), analytically pure product was isolated by column chromatography on silica gel (100–200 mesh, petroleum ether/EtOAc = 100:0–10:1).

Spectral Data of Unsymmetrical Ethers

(1-Propoxyethyl)benzene[22] (3a)

Yield 72 mg, 83%. Colorless liquid. IR (DCM): 2973, 2874, 1451, 1206, 1105, 1028, 1069, 889, 760, 700, 556 cm–1. 1H NMR (CDCl3): δ 7.20–7.27 (m, 5H), 4.31 (q, 1H, J = 7 Hz), 3.18 (t, 2H, J = 7 Hz), 1.48–1.53 (m, 2H), 1.36 (d, 3H, J = 6.3 Hz), 0.82 (t, 3H, J = 7.7 Hz). 13C {1H} NMR (CDCl3): δ 144.4, 128.5, 127.4, 126.2, 78.0, 70.5, 24.4, 23.3, 10.8.

(1-(Pentyloxy)ethyl)benzene[23] (3b)

Yield 79 mg, 83%. Yellow liquid. IR (DCM): 2929, 2859, 1451, 1102, 1069, 759, 699 cm–1. 1H NMR (CDCl3): δ 7.23–7.27 (m, 5H), 4.30 (q, 1H, J = 7 Hz), 3.21 (t, 2H, J = 6.3 Hz), 1.47–1.50 (m, 2H), 1.35 (d, 3H, J = 6.3 Hz), 1.19–1.24 (m, 4H), 0.80 (t, 3H, J = 7 Hz). 13C {1H} NMR (CDCl3): δ 144.5, 128.5, 127.4, 126.2, 78.0, 68.9, 29.8, 28.5, 24.4, 22.7, 14.2. HRMS (ESI) m/z: [M + Na]+ calcd for C13H20ONa, 215.1406; found 215.1397.

(1-Propoxypropyl)benzene[24] (3c)

Yield 65 mg, 75%. Yellow liquid. IR (DCM): 2962, 2875, 1453, 1355, 1260, 1097, 1083, 755, 700 cm–1. 1H NMR (CDCl3): δ 7.17–7.26 (m, 5H), 4.02 (t, 1H, J = 6.3 Hz), 3.11–3.22 (m, 2H), 1.55–1.77 (m, 2H), 1.47–1.52 (m, 2H), 0.80–0.83 (m, 6H). 13C {1H} NMR (CDCl3): δ 143.3, 128.3, 127.4, 126.8, 83.8, 70.7, 31.4, 23.2, 10.8, 10.5.

(1-(Hexyloxy)propyl)benzene (3d)

Yield 86 mg, 78%. Yellow liquid. IR (DCM): 2959, 2859, 1453, 1341, 1202, 1100, 1028, 754, 700 cm–1. 1H NMR (CDCl3): δ 7.17–7.27 (m, 5H), 4.01 (t, 1H, J = 6.3 Hz), 3.14–3.25 (m, 2H), 1.57–1.75 (m, 2H), 1.48 (t, 2H, J = 7 Hz), 1.16–1.26 (m, 6H) 0.78–0.82 (m, 6H). 13C {1H} NMR (CDCl3): δ 143.3, 128.3, 127.4, 126.8, 83.9, 69.1, 31.8, 31.4, 30.0, 26.0, 22.8, 14.2, 10.5. HRMS (ESI) m/z: [M + Na]+ calcd for C15H24ONa, 243.1719; found 243.1721.

1-Methyl-4-(1-propoxyethyl)benzene (3e)

Yield 81 mg, 91%. Colorless liquid. IR (DCM): 2926, 1513, 1452, 1093, 816, 542 cm–1. 1H NMR (CDCl3): δ 7.07–7.13 (m, 4H), 4.28 (q, 1H, J = 6.3 Hz), 3.16 (t, 2H, J = 7 Hz), 2.27 (s, 3H), 1.47–1.52 (m, 2H), 1.34 (d, 3H, J = 6.3 Hz), 0.81 (t, 3H, J = 7 Hz). 13C {1H} NMR (CDCl3): δ 141.4, 137.0, 129.2, 126.2, 77.8, 70.4, 24.4, 23.3, 21.3, 10.8. HRMS (ESI) m/z: [M + Na]+ calcd for C12H18ONa, 201.1249; found 201.1259.

1-Methyl-4-(1-(pentyloxy)ethbyl)benzene (3f)

Yield 95 mg, 93%. Colorless liquid. IR (DCM): 2930, 2860, 1513, 1454, 1102, 1061, 1020, 817, 726, 555 cm–1. 1H NMR (CDCl3): δ 7.07–7.13 (m, 4H), 4.27 (q, 1H, J = 6.3 Hz), 3.17–3.22 (m, 2H), 2.27 (s, 3H), 1.48 (t, 2H, J = 7 Hz), 1.34 (d, 3H, J = 7 Hz), 1.18–1.23 (m, 4H), 0.79–0.81 (m, 3H). 13C {1H} NMR (CDCl3): δ 141.4, 137.0, 129.2, 126.2, 77.8, 68.8, 29.8, 28.5, 24.4, 22.7, 21.3, 14.2. HRMS (ESI) m/z: [M + Na]+ calcd for C14H22ONa, 229.1563; found 229.1564.

1-(1-(Hexyloxy)ethyl)-4-methylbenzene (3g)

Yield 89 mg, 81%. Colorless liquid. IR (DCM): 2930, 2859, 1513, 1454, 1102, 946, 816, 724, 555 cm–1. 1H NMR (CDCl3): δ 7.07–7.13 (m, 4H), 4.27 (q, 1H, J = 6.3 Hz), 3.18–3.20 (m, 2H), 2.27 (s, 3H), 1.45–1.50 (m, 2H), 1.34 (d, 3H, J = 7 Hz), 1.15–1.25 (m, 6H), 0.79 (t, 3H, J = 7.7 Hz). 13C {1H} NMR (CDCl3): δ 141.4, 137.0, 129.2, 126.2, 77.8, 68.8, 31.8, 30.1, 26.0, 24.4, 22.8, 21.3, 14.2. HRMS (ESI) m/z: [M + Na]+ calcd for C15H24ONa, 243.1719; found 243.1700.

1,3,5-Trimethyl-2-(1-(pentyloxy)ethyl)benzene (3h)

Yield 52 mg, 45%. Colorless liquid. IR (DCM): 2935, 2859, 1510, 1450, 1102, 946, 816, 724, 555 cm–1. 1H NMR (CDCl3): δ 6.75 (s, 2H), 5.84–6.17 (m, 2H), 4.06–4.06 (m, 1H), 2.28 (s, 6H), 2.16 (d, 11H, J = 9.1 Hz), 1.41–1.43 (m, 3H). 13C {1H} NMR (CDCl3): δ 139.0, 138.7, 136.5, 135.9, 135.7, 135.4, 134.7, 130.1, 128.6, 125.7, 37.3, 21.4, 21.0, 20.8, 18.2. HRMS (ESI) m/z: [M + Na]+ calcd for C16H26ONa, 257.1875; found 257.1885.

1-Chloro-4-(1-methoxyethyl)benzene[25] (3i)

Yield 77 mg, 91%. Colorless liquid. IR (DCM): 2924, 2852, 1593, 1490, 1404, 1373, 1092, 1011, 967, 808, 826, 536 cm–1. 1H NMR (CDCl3): δ 7.10–7.22 (m, 4H), 3.51–3.55 (m, 1H), 1.36 (d, 3H), 1.18 (s, 3H). 13C {1H} NMR (CDCl3): δ 143.9, 136.0, 135.5, 132.9, 132.1, 128.80, 128.79, 128.77, 127.9, 127.5, 42.1, 29.8, 21.2.

1-(1-(Benzyloxy)ethyl)-4-methylbenzene (3j)

Yield 105 mg, 93%. Yellow liquid. IR (DCM): 2975, 2863, 1453, 1095, 1057, 817, 735, 697, 546 cm–1. 1H NMR (CDCl3): δ (ppm) 7.07–7.27 (m, 9H), 4.40 (q, 1H, J = 6.3 Hz), 4.36 (d, 1H, J = 11.9 Hz), 4.20 (d, 1H, J = 11.9 Hz), 2.29 (s, 3H), 1.39 (d, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 140.8, 138.9, 137.3, 129.3, 128.5, 127.6, 126.5, 74.4, 70.3, 24.4, 21.3. HRMS (ESI) m/z: [M + Na]+ calcd for C16H18ONa, 249.1249; found 249.1234.

1-Methyl-4-(1-((4-methylbenzyl)oxy)ethyl)benzene (3k)

Yield 109 mg, 91%. Yellow liquid. IR (DCM): 2923, 2861, 1513, 1451, 1203, 1092, 1054, 903, 817, 555 cm–1. 1H NMR (CDCl3): δ 7.05–7.18 (m, 8H), 4.37 (q, 1H, J = 6.3 Hz), 4.32 (d, 1H, J = 11.9 Hz), 4.15 (d, 1H, J = 11.9 Hz), 2.28 (s, 3H), 2.26 (s, 3H), 1.37 (d, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 140.9, 137.23, 137.22, 135.8, 129.3, 129.1, 128.0, 126.5, 76.9, 70.1, 24.4, 21.3, 21.28. HRMS (ESI) m/z: [M + Na]+ calcd for C17H20ONa, 263.1406; found 263.1392.

1-Fluoro-4-((1-(p-tolyl)ethoxy)methyl)benzene (3l)

Yield 100 mg, 82%. Yellow liquid. IR (DCM): 2974, 2863, 1602, 1510, 1451, 1220, 1055, 1016, 819, 555 cm–1. 1H NMR (CDCl3): δ 6.90–7.19 (m, 8H), 4.36 (q, 1H, J = 6.3 Hz), 4.29 (d, 1H, J = 11.2 Hz), 4.15 (d, 1H, J = 11.2 Hz), 2.27 (s, 3H), 1.38 (d, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 163.0, 161.6, 140.5, 137.3, 134.48, 134.46, 129.5, 129.4, 129.2, 126.3, 115.2, 115.1, 76.9, 69.5, 24.2, 21.2. HRMS (ESI) m/z: [M + Na]+ calcd for C16H17FONa, 267.1156; found 267.1167.

4-((1-(4-Methoxyphenyl)ethoxy)methyl)benzonitrile (3m)

Yield 92 mg, 69%. Colorless liquid. IR (DCM): 2972, 2227, 1606, 1453, 1172, 1087, 1034, 818, 547 cm–1. 1H NMR (CDCl3): δ 7.55 (q, 2H, J = 4.9 Hz), 7.34 (t, 2H, J = 7.7 Hz), 7.19–7.20 (m, 2H), 6.84 (q, 2H, J = 4.9 Hz), 4.39 (q, 1H, J = 6.3 Hz), 4.36 (d, 1H, J = 13.3 Hz), 4.28 (d, 1H, J = 12.6 Hz), 3.75 (s, 3H), 1.43 (d, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 159.4, 144.6, 135.1, 132.3, 127.9, 127.6, 119.1, 114.1, 111.2, 77.7, 69.3, 55.4, 24.1. HRMS (ESI) m/z: [M + Na]+ calcd for C17H17NO2Na, 290.1151; found 290.1149.

4-((1-(p-Tolyl)ethoxy)methyl)benzonitrile (3n)

Yield 114 mg, 91%. Colorless liquid. IR (DCM): 2972, 2237, 1606, 1453, 1172, 1087, 1034, 818, 547 cm–1. 1H NMR (CDCl3): δ 7.09–7.52 (m, 8H), 4.38 (q, 1H, J = 6.3 Hz), 4.36 (d, 1H, J = 13.3 Hz), 4.26 (d, 1H, J = 12.6 Hz), 2.27 (s, 3H), 1.41 (d, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 144.5, 140.1, 137.6, 132.2, 129.4, 127.8, 126.3, 119.0, 111.1, 78.0, 69.3, 24.1, 21.2. HRMS (ESI) m/z: [M + Na]+ calcd for C17H17NONa, 274.1202; found 274.1211.

1-Methoxy-4-(1-((4-nitrobenzyl)oxy)ethyl)benzene (3o)

Yield 60 mg, 45%. Yellow liquid. IR (DCM): 2972, 2836, 2227, 1613, 1513, 1245, 1091, 1035, 832, 548 cm–1. 1H NMR (CDCl3): δ 8.11 (d, 2H, J = 9.1 Hz), 7.40 (d, 2H, J = 9.1 Hz), 7.12–7.18 (m, 4H), 4.41–4.42 (m, 2H), 4.33 (d, 1H, J = 13.3 Hz), 2.29 (s, 3H), 1.44 (d, 3H, J = 6.3 Hz. 13C {1H} NMR (CDCl3): δ 147.4, 146.6, 140.0, 137.7, 129.5, 127.8, 126.4, 123.7, 78.1, 69.1, 24.2, 21.3. HRMS (ESI) m/z: [M + Na]+ calcd for C16H17NO4Na, 310.1049; found 310.1057.

1-(1-(Hept-2-yn-1-yloxy)ethyl)-4-methylbenzene (3p)

Yield 109 mg, 95%. Yellow liquid. IR (DCM): 2931, 2871, 2281, 2235, 1445, 1369, 1266, 1085, 1051, 817, 729, 547 cm–1. 1H NMR (CDCl3): δ 7.07–7.15 (m, 4H), 4.52 (q, 1H, J = 7 Hz), 3.97 (d, 1H, J = 14.7 Hz), 3.78 (d, 1H, J = 15.4 Hz), 2.27 (s, 3H), 2.14 (q, 2H, J = 4.9 Hz), 1.40–1.44 (m, 2H), 1.38 (d, 3H, J = 7 Hz), 1.31–1.36 (m, 2H), 0.84 (t, 3H, J = 7.7 Hz). 13C {1H} NMR (CDCl3): δ 139.9, 137.4, 129.3, 126.6, 86.7, 56.2, 30.8, 23.9, 22.1, 21.3, 18.6, 13.7. HRMS (ESI) m/z: [M + Na]+ calcd for C16H22ONa, 253.1562; found 253.1545.

2-((1-(4-Methoxyphenyl)ethoxy)methyl)tetrahydrofuran (3q)

Yield 47 mg, 40%. Colorless liquid. IR (DCM): 2931, 2836, 1606, 1510, 1247, 1175, 1033, 832, 545 cm–1. 1H NMR (CDCl3): δ 7.21–7.11 (d, 4H, J = 9.1 Hz), 6.75–6.79 (m, 4H), 6.13–6.16 (m, 2H), 3.48–3.82 (m, 7H), 1.35 (d, 3H, J = 7 Hz). 13C {1H} NMR (CDCl3): δ 158.9, 158.1, 138.1, 133.7, 130.6, 128.3, 127.7, 127.3, 114.05, 113.97, 55.44, 55.43, 41.8, 21.6. HRMS (ESI) m/z: [M + Na]+ calcd for C14H20O3Na, 259.1305; found 259.1282.

(3-(tert-Butoxy)propyl)benzene[26] (3r)

Yield 38 mg, 40%. Light yellow liquid. IR (DCM): 2923, 2853, 1732, 1454, 1361, 1259, 1084, 801, 698 cm–1. 1H NMR (CDCl3): δ 7.09–7.21 (m, 5H), 3.29 (t, 2H, J = 6.3 Hz), 2.61 (t, 2H, J = 7.7 Hz), 1.76–1.80 (m, 2H), 1.11 (s, 9H). 13C {1H} NMR (CDCl3): δ 142.4, 128.6, 128.4, 125.8, 72.7, 60.9, 32.6, 32.2, 27.7.

(1-(But-3-en-1-yloxy)ethyl)benzene (4a)

Yield 139 mg, 79%. Colorless liquid. IR (DCM): 2976, 2860, 1641, 1451, 1103, 912, 760, 554 cm–1. 1H NMR (CDCl3): δ 7.17–7.27 (m, 5H), 5.70–5.75 (m, 1H), 4.98 (d, 1H, J = 17.5 Hz), 4.93 (dd, 1H, J = 7 Hz), 4.32 (q, 1H, J = 7 Hz), 3.26–3.29 (m, 2H), 2.25 (q, 2H, J = 7 Hz), 1.36 (d, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 144.2, 135.5, 128.6, 128.5, 127.5, 126.3, 116.3, 78.1, 68.1, 34.5, 24.3. MS (ESI): [M + Na]+ calcd for C12H16ONa, 199.1093; found 199.1099.

(1-(Hex-3-yn-1-yloxy)ethyl)benzene (4b)

Yield 161 mg, 80%. Colorless liquid. IR (DCM): 3083, 2974, 2231, 1450, 1319, 1204, 1102, 761, 700 cm–1. 1H NMR (CDCl3): δ 7.20–7.26 (m, 5H), 4.36 (q, 1H, J = 7 Hz), 3.30–3.34 (m, 2H), 2.31–2.35 (m, 2H), 2.04–2.07 (m, 2H), 1.36 (m, 3H, J = 6.3 Hz), 1.02 (t, 3H, J = 7.7 Hz). 13C {1H} NMR (CDCl3): δ 143.9, 128.5, 127.5, 126.3, 82.8, 78.2, 77.0, 76.2, 67.4, 24.3, 20.4, 14.3, 12.5. MS (ESI): [M + Na]+ calcd for C14H18ONa, 225.1249; found 225.1258.

1-Fluoro-2-((1-phenylethoxy)methyl)benzene (4c)

Yield 218 mg, 95%. Colorless liquid. IR (DCM): 3029, 2975, 1492, 1370, 1230, 1218, 1109, 1091, 908, 700 cm–1. 1H NMR (CDCl3): δ 7.05–7.50 (m, 9H), 4.57–4.60 (m, 1H), 4.46–4.54 (m, 2H), 1.54–1.56 (m, 3H). 13C {1H} NMR (CDCl3): δ 161.5, 160.1, 143.7, 130.1, 129.3, 128.6, 127.7, 126.4, 124.15, 124.14, 115.3, 115.2, 77.9, 64.18, 64.16, 24.3. MS (ESI): [M + Na]+ calcd for C15H15FONa, 253.0999; found 253.0968.

((2-Ethylbutoxy)methylene)dibenzene (4d)

Yield 219 mg, 82%. Colorless liquid. IR (DCM): 2930, 2960, 1493, 1302, 1074, 738, 701 cm–1. 1H NMR (CDCl3): δ 7.15–7.27 (m, 10H), 5.21 (s, 1H), 3.25–3.26 (m, 2H), 1.43–1.46 (m, 1H), 1.27–1.38 (m, 4H), 0.76–0.78 (m, 6H). 13C {1H} NMR (CDCl3): δ 143.0, 128.4, 127.4, 127.1, 83.8, 71.4, 41.7, 23.6, 11.3. MS (ESI): [M + Na]+ calcd for C19H24ONa, 291.1719; found 291.1722.

(But-3-en-1-yloxy)methylene)dibenzene (4e)

Yield 209 mg, 88%. Colorless liquid. IR (DCM): 3027, 2858, 1640, 1493, 1304, 1095, 914, 740 cm–1. 1H NMR (CDCl3): δ 7.14–7.28 (m, 10H), 5.75–5.81 (m, 1H), 5.27 (s, 1H), 5.01 (dd, 1H, J = 15.4 Hz), 4.95 (dd, 1H, J = 9.8 Hz), 3.42 (t, 2H, J = 6.3 Hz), 2.83 (q, 2H, J = 7 Hz). 13C {1H} NMR (CDCl3): δ 142.5, 135.5, 128.51, 128.50, 127.5, 127.1, 116.4, 83.7, 68.6, 34.5. MS (ESI): [M + Na]+ calcd for C17H18ONa, 261.1250; found 261.1214.

(3-Methoxybutoxy)methylene)dibenzene (4f)

Yield 218 mg, 81%. Colorless liquid. IR (DCM): 3060, 2968, 1600, 1453, 1186, 1090, 1073, 740, 523 cm–1. 1H NMR (CDCl3): δ 7.13–7.26 (m, 9H), 5.25 (s, 1H), 3.41–3.49 (m, 3H), 3.20 (s, 3H), 1.64–1.78 (m, 2H), 1.05 (m, 3H, J = 6.3 Hz). 13C {1H} NMR (CDCl3): δ 142.6, 128.4, 128.4, 127.5, 127.4, 127.1, 127.0, 83.8, 74.2, 65.9, 56.1, 37.0, 19.3. MS (ESI): [M + Na]+ calcd for C18H22ONa, 293.1512; found 293.1517.

(E)-Prop-2-ene-1,1,3-triyltribenzene[27] (5)

Yield 94 mg, 71%. White Solid. IR (DCM): 3024, 2922, 1599, 1493, 1076, 1029, 968, 745 cm–1. 1H NMR (CDCl3): δ 7.21–7.37 (m, 15H), 6.68 (dd, 1H, J = 16 Hz, 7.6 Hz ), 4.90 (d, 1H, J = 7.6 Hz).

Mechanistic Study: Procedure for the Synthesis of Unsymmetrical Ether (3f) from Symmetrical Ether (1c)

4,4′-(Oxybis(ethane-1,1-diyl))bis(methylbenzene) (0.25 mmol), 1-pentanol (0.5 mmol), ammonium chloride (0.7 mg, 0.0125 mmol), and Fe(OTf)3 (6.3 mg, 5 mol %) in dichloromethane (2 mL) were charged in a sealed tube with a stirrer bar under open atmosphere. After completion, the reaction mixture was purified by column chromatography on silica gel (petroleum ether/EtOAc 80/1 → 80/4) to provide 3f in 70% yield.

Procedure for Intermolecular Competition Experiment

Representative procedure of the catalysis experiment was followed. 1-(p-Tolyl)ethanol (0.5 mmol), 4-methylbenzyl alcohol (0.5 mmol), 4-cyanobenzyl alcohol (0.5 mmol), ammonium chloride (1.3 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a sealed tube with a stirrer bar under open atmosphere. The reaction mixture was stirred at 45 °C for 12 h. After completion, the reaction mixture was purified by column chromatography on silica gel (petroleum ether/EtOAc 80/1 → 80/4) to yield the coupled products in different yields (Scheme c). The ratio of 3k to 3o is 1.15:1.

Investigation of the Effect of Tetraethyl Ammonium Chloride in Catalysis

1-Phenylethanol (0.5 mmol), tetraethyl ammonium chloride (8.2 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a round-bottom flask with a stirrer bar under open atmosphere. The reaction mixture was stirred at room temperature for 2 h and analyzed by TLC and GC.

Study of Reversibility in Catalysis upon Reaction of Symmetrical Ethers 1a and 1i in the Presence of Fe(OTf)3

(Oxybis(ethane-1,1-diyl))dibenzene (1a) (0.25 mmol), 1i (0.25 mmol), ammonium chloride (0.7 mg, 5 mol %), and Fe(OTf)3 (6.3 mg, 5 mol %) in dichloromethane (2 mL) were charged in a round-bottom flask with a stirrer bar under open atmosphere. The reaction mixture was stirred at room temperature for 2 h and analyzed by TLC and GC. After completion, the reaction mixture was purified by column chromatography on silica gel, which provided alkene 5 in 71% (94 mg) yield.

Investigation of the Effect of Molecular Sieves in Catalysis

1-Phenylethanol (0.5 mmol), 1-pentanol (0.5 mmol), ammonium chloride (1.5 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a round-bottom flask with a stirrer bar under open atmosphere. The reaction mixture was stirred at 45 °C for 12 h and analyzed by TLC and GC. After completion, the reaction mixture was purified by column chromatography on silica gel, which provided 3b in 55% (51 mg) yield.

Procedure for Monitoring Etherification Reaction (Symmetrical Ether)

Benzyl alcohol (0.5 mmol), ammonium chloride (1.3 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a round-bottom flask with a stirrer bar under open atmosphere. The reaction mixture was stirred at 0 °C and allowed to warm at room temperature. At regular intervals, an aliquot of sample was withdrawn to the GC vial. The sample was diluted with acetone and subjected to GC analysis. The concentration of the product 1c obtained in each sample was determined with respect to the internal standard n-dodacane.

Procedure for Monitoring Etherification Reaction (Unsymmetrical Ether)

Benzyl alcohol (0.5 mmol), aliphatic alcohol (0.5 mmol), ammonium chloride (1.3 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a sealed tube with a stirrer bar under open atmosphere. The reaction mixture was stirred at 45 °C.

At regular intervals, an aliquot of sample was withdrawn to the GC vial. The sample was diluted with acetone and subjected to GC analysis. The concentration of the product 3f obtained in each sample was determined with respect to the internal standard n-dodacane.

Sample Preparation of Fe(OTf)3 for EPR Analysis

Fe(OTf)3 (0.025 mmol) was dissolved in DCM (2 mL). The sample solutions (200 μL) were transferred into borosilicate glass capillary tubes with an internal diameter of 2 mm, which was positioned centrally in the EPR cavity.

Sample Preparation of Reaction Mixture for EPR Analysis

1-Phenylethanol (0.25 mmol), 1-propanol (0.25 mmol), ammonium chloride (0.65 mg, 0.025 mmol), and Fe(OTf)3 (12.6 mg, 5 mol %) in dichloromethane (2 mL) were charged in a round-bottom flask with a stirrer bar under open atmosphere. The reaction mixture was stirred at room temperature for 1 h. At regular intervals, an aliquot of sample was withdrawn and the reaction mixture solutions (200 μL) were transferred into borosilicate glass capillary tubes with 2 mm internal diameter, which was positioned centrally in the EPR cavity.

EPR Measurement Parameters

Frequency = 9.85 GHz; modulation amplitude = 4 G; receiver gain = 2 × 102; modulation frequency = 100 kHz; conversion time = 10 ms; sweep width = 3000 G; center field = 2500 G; power = 5.35 e–1 mW.