Nickel-Catalyzed Reductive Etherification of Aldehydes at Room

Nickel-Catalyzed Reductive Etherification of Aldehydes at Room Temperature: C–O vs C–C Bond Formation. Sajjad Rahimi†, Farhad Panahi†‡ , Mar...
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Note Cite This: J. Org. Chem. 2018, 83, 973−979

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Nickel-Catalyzed Reductive Etherification of Aldehydes at Room Temperature: C−O vs C−C Bond Formation Sajjad Rahimi,† Farhad Panahi,*,†,‡ Marzieh Bahmani,† and Nasser Iranpoor*,† †

Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran Mahshahr Campus, Amirkabir University of Technology, Mahshahr, Iran

‡

S Supporting Information *

ABSTRACT: The reaction of secondary and tertiary benzyl alcohols activated by 2,4,6-trichloro-1,3,5-triazine (TCT) with aldehydes in the presence of NiCl2·dmg as a precatalyst in ethylene glycol afforded ethers at room temperature. A selective C−O vs C−C bond formation was observed for the secondary and tertiary benzyl alcohols in comparison with primary ones.

S

TiO214 were reported as efficient catalysts for this purpose. A method was also reported by Barluenga et al. on the metal-free reductive coupling of tosylhydrazones with alcohols or phenols, which is another route for reductive etherification of carbonyl compounds.15 Previously, we reported the Ni-catalyzed coupling of benzylic substrates and aldehydes for the one-pot synthesis of benzylic alcohols.16 Also, we have illustrated the synthesis of amides using Ni-catalyzed reductive coupling of benzyl halides and carbodiimides.17 In this study, we found that the etherification of aldehydes could be accomplished simply at room temperature in ethylene glycol (EG) as both a solvent and a reducing agent (Scheme 1). As far as we know, there is no report in the literature on the Ni-catalyzed reductive etherification of aldehydes. The reaction conditions were optimized using a model reaction containing (1-chloroethyl)benzene (1a) and benzaldehyde (2a). The obtained results of the optimization study are demonstrated in Table 1. As shown in Table 1, in the presence of Ni(II) precatalyst and Zn as a reducing agent in ethylene glycol as a solvent, 81% of the corresponding ether was obtained (Table 1, entry 1). By changing the reducing agent to Mn, the reaction yield was decreased to 76%, demonstrating that Zn is more efficient than Mn as a reducing agent (Table 1, entry 2). In the absence of the Ni catalyst, no product was obtained representing that this is a Ni-catalyzed process (Table 1, entry 3). Since EG has already been used as a reducing agent,18 we decided to run the reaction in the absence of a metal reductant.

imple and efficient synthesis of ethers as an important class of organic compounds is still a subject of broad attention. The most used etherification process relies on the Williamson method.1 In this protocol, alcohols/phenols react with alkyl halides under very harsh and basic conditions. The competing elimination in the case of secondary and tertiary halides and the use of basic conditions decrease the generality and functional group tolerance of the method. Also, in this reaction, alkyl halides as a toxic and expansive material were employed. Acidcatalyzed condensation of alcohols is another approach for the synthesis of ethers. This method also suffers from some limitations including sensitivity to the steric bulk of the substrates, limitation to the synthesis of only symmetrical ethers, and the use of harsh conditions, which lead to the formation of byproducts such as olefins.2 However, a few selective methods have been developed for the synthesis of some ether compounds.3−7 One of the most promising approaches on the synthesis of ethers is reductive coupling of carbonyl compounds and silyl ethers in the presence of a hydrogen source and a Lewis catalyst.8 This strategy is efficiently suitable for the synthesis of unsymmetrical ethers. Silane-reductive etherification is another version of this approach, in which silane was employed as a reducing agent.9 In this method, TMS-OTf was used as a catalyst, which is moisture sensitive with difficult handling. In order to overcome the existing problems, other catalysts including Cu(OTf)2,10a FeCl3,10b TMSI,8c tris(pentafluorophenyl)borane,8h and RuHLncomplex11 were used instead of TMS-OTf. In some cases, the reductive etherification of carbonyl compounds was performed step-by-step with long reaction times.8,10,12 This reaction has also been performed under the heterogeneous conditions, and H−Au(III)13 and Au/ © 2017 American Chemical Society

Received: September 11, 2017 Published: December 28, 2017 973

DOI: 10.1021/acs.joc.7b02281 J. Org. Chem. 2018, 83, 973−979

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Scheme 1. Ni-Catalyzed Reductive Etherification of Aldehydes at Room Temperature Using Ethylene Glycol As a Reducing Agent

Table 1. Optimization of the Reaction Conditionsa

entry

Ni catalyst

reductant

solvent

yield 3a (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

NiCl2·5H2O NiCl2·5H2O none NiCl2·5H2O NiCl2·5H2O NiCl2·5H2O NiCl2·5H2O NiBr2 NiCl2(dppf) NiCl2(dppp) NiCl2(PPh3)2 NiCl2·glyme NiCl2·dmg Ni(PPh3)2(CO)2 NiCl2·dmg NiCl2·dmg NiCl2·dmg

Zn Mn Zn none none none none EG EG EG EG EG EG none EG EG EG

EG EG EG EG glycerol PEG-200 DMF EG EG EG EG EG EG DMF EG EG EG

81 76 0 78 71 10 0 76 75 73 62 79 83 65 60c 84d 74e

a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), MgCl2 (2.0 mmol), reductant (3.0 mmol), [Ni] (10 mol %), and solvent (3.0 mL). bIsolated yield. c5 mol % of catalyst was used. d12 mol % of catalyst was used. e8 mol % of catalyst was used.

Scheme 2. Ni-Catalyzed Reductive Etherification Using Different Benzyl Electrophiles

1, entries 8−13). In order to show that this reaction proceeds through a Ni(0)-catalyzed process, Ni(PPh3)2(CO)2 was used as a catalyst and 65% of the desired product was obtained (Table 1, entry 14). The amount of the precatalyst was also optimized, and 10 mol % was recognized as the optimum amount (Table 1, entries 15−17). In this way, entry 13 of Table 1 was selected as the most optimized condition for the Nicatalyzed reductive etherification of aldehydes. We initially examined the reactivity of some other benzyl electrophiles toward the reductive etherification reaction with benzaldehyde in order to benchmark their reactivity in this protocol (Scheme 2).

Hopefully, the product was obtained in a remarkable yield of 87% (Table 1, entry 4). In order to show the role of EG as a reducing agent, different experiments were conducted (Table 1, entries 5−7). For example, glycerol showed a reductant activity and 71% of the ether product was produced,19 while in PEG20020 the reaction yield was decreased to 10% and in DMF no product was detected. Thus, the existence of both Ni catalyst and EG as a reducing agent for this process is required. Considering the role of EG as both a solvent and a reducing agent, the optimization study was continued. Different Ni-catalysts21 were checked, and NiCl2·dmg was selected as the most efficient precatalyst for this process (Table 974

DOI: 10.1021/acs.joc.7b02281 J. Org. Chem. 2018, 83, 973−979

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The Journal of Organic Chemistry Scheme 3. Ni-Catalyzed Reductive Coupling of Activated Primary Benzyl Alcohol by TCT and Benzaldehyde

Scheme 4. Products of Nickel-Catalyzed Reductive Coupling of Primary, Secondary, and Tertiary Benzylic C−O Electrophiles and Aldehydea

a

Reaction conditions: TAT (0.35 mmol), aldehyde (1.0 mmol), MgCl2 (2.0 mmol), EG (3.0 mL), NiCl2·dmg (10 mol %), rt, 24 h.

single step by the reaction of alcohol with 2,4,6-trichloro-1,3,5triazine (TCT, cyanuric chloride). TCT easily reacts with 3 equiv of alcohol to produce 2,4,6tris(alkoxy)-1,3,5-triazine (TAT). The C−O bond in TAT is longer than that alcohol, representing that TCT acts as a C−O bond activating agent (Scheme 1).22 In fact, TAT is an alkyl C−O electrophile, which can be used instead of halides, allowing direct application of alcohols in organic reactions.23 In

As shown in Scheme 2, it is possible to obtain the reaction yield of 83−84% using chloride, bromide, tosylate, and triflate electrophiles. No product formation was observed for benzyl alcohol under our optimized conditions. A maximum reaction yield was observed for 2,4,6-tris(1-phenylethoxy)-1,3,5-triazine (X for this substrate is considered OTA). This class of alkyl C− O electrophiles is readily available and can be prepared in a 975

DOI: 10.1021/acs.joc.7b02281 J. Org. Chem. 2018, 83, 973−979

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The Journal of Organic Chemistry Scheme 5. Competing Experiments

substrates and gave the ether product in moderate to good yields. Overall, this methodology is suitable for the synthesis of bulky substituted benzylic ethers. Since benzyl ethers can be used as a protected group in multistep synthesis,24 our approach could have synthetic significance for the protection of aldehyde groups. It should be mentioned that the direct conversion of an aldehyde group to ether moiety could be interesting with synthetic applications in organic chemistry. Also, different primary benzylic substrates can be coupled with aldehydes in order to synthesize diverse alcohol products (Scheme 4, products 4b−i). In fact, in this method, there is a competition between the nickel-catalyzed carbon−carbon bond formation reaction and the reductive etherification by change of primary to secondary/tertiary benzylic substrates. A series of competing experiments were also carried out to establish the selectivity trends (Scheme 5). First, a competing reaction was performed between a ketone (acetophenone) and aldehyde in the reaction with 1-phenylethanol. It was found that no ether product was produced with a ketone under the optimized conditions. Additionally, we performed two other competing experiments between aliphatic and aromatic

this study, TAT was used as a new C−O electrophile in a reductive coupling reaction with aldehydes and it efficiently resulted in the production of ether product. However, what is interesting here is that, by the use of primary benzyl alcohols, the obtained product is not ether and instead an benzylic alcohol is produced (Scheme 3). In fact, there is selectivity between the C−O and C−C bond formation reactions. In order to confirm and generalize this observation, different primary, secondary, and tertiary benzylic substrates were reacted with different aldehydes and the obtained results confirmed our primary observation. The obtained results demonstrated that, under our optimized conditions, the reaction of aromatic aldehydes with secondary and tertiary activated benzylic alcohols shows excellent C−O bond formation selectivity and produces the corresponding ether (Scheme 4). As shown in Scheme 4, it is possible to synthesize different unsymmetrical ether compounds through the reaction of aldehydes with secondary or tertiary benzyl alcohols. Aldehydes with both electron-donating and electron-withdrawing groups underwent this reaction with secondary and tertiary benzylic 976

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stirred in dry THF (5 mL) for 1 h at room temperature. Then 0.35 mmol of TCT was added to the reaction mixture, and stirring was continued for 2 h. The precipitated solid was added to the reaction mixture containing aldehyde (1.0 mmol), MgCl2 (2.0 mmol), NiCl2· dmg (10.0 mol %), and ethylene glycol (3.0 mL). The mixture was stirred at rt for 24 h under these conditions. After completion of the reaction as confirmed by TLC, ethyl acetate (25 mL) and water (25 mL) were added to the reaction mixture. After separation of the organic layer from water, the aqueous phases were extracted with ethyl acetate (2 × 25 mL) again. The combined organic layers were then dried over anhydrous Na2SO4, filtered, and concentrated under a vacuum to yield the crude product. The crude product was purified by column chromatography (n-hexane/ethyl acetate) to obtain the desired pure compound. Typical Procedure for the Large-Scale Ni-Catalyzed Addition of Benzyl Alcohols to Aldehydes Using TCT Reagent. In a conical flask (200 mL), a mixture of 4-methoxybenzyl alcohol (10 mmol) and NaH (12 mmol) was stirred in dry THF (50 mL) for 2 h at room temperature. Subsequently, 3.5 mmol of TCT was added to the reaction mixture, and stirring was continued for 5 h. The precipitated solid was added to the reaction mixture containing 2methoxybenzaldehyde (10 mmol), MgCl2 (20 mmol), NiCl2·dmg (1 mmol), and ethylene glycol (30 mL). The mixture was stirred at rt for 24 h. Afterward, ethyl acetate (300 mL) and water (300 mL) were added to the reaction mixture. The organic layer was separated, and the aqueous phases were extracted with ethyl acetate (2 × 50 mL) again. The organic layer was dried over anhydrous Na2SO4 and evaporated. In order to obtain a pure product, it was purified by column chromatography using n-hexane/ethyl acetate (10:5) as an eluent (Rf = 0.42). The pure product was obtained in 74% (1.91 g) yield as a light yellow oil. Spectral Data for Synthesized Compounds. (1-(Benzyloxy)ethyl)benzene (3a). Light yellow oil, Rf (n-hexane/EtOAc 10:1) = 0.66. Yield: 73% (155 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.41 (d, J = 5 Hz, 3H), 4.22 (d, J = 12.5 Hz, 1H), 4.36−4.47 (m, 2H), 7.18−7.31 (m, 10H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.2, 70.3, 77.2, 126.3, 127.4, 127.5, 127.7, 128.3, 128.5, 138.6, 143.7. MS: m/z 212 (35, M+). Anal. Calcd for C15H16O (212.28): C, 84.87; H, 7.60. Found: C, 84.80; H, 7.53. 1-Isopropyl-4-((1-phenylethoxy)methyl)benzene (3b). Pale yellow oil, Rf (n-hexane/EtOAc 10:1) = 0.60. Yield: 75% (190 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.16 (d, J = 7.5 Hz, 6H), 1.40 (d, J = 7.5 Hz, 3H), 2.80−2,97 (m, 1H), 4.18 (d, J = 12.5 Hz, 1H), 4.33 (d, J = 12.5 Hz, 1H), 4.43 (q, J = 7.5 Hz, 1H), 7.10−7.30 (m, 9H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.0, 24.3, 33.8, 70.2, 77.2, 126.3, 126.4, 127.4, 127.8, 128.4, 136.4, 143.8, 147.8. MS: m/z 254 (65, M+), 255 (12, M + 1). Anal. Calcd for C18H22O (254.36): C, 84.99; H, 8.72. Found: C, 84.91; H, 8.65. 1-Methoxy-4-((1-phenylethoxy)methyl)benzene (3c). Light yellow oil, Rf (n-hexane/EtOAc 10:2) = 0.52. Yield: 72% (174 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.38 (d, J = 7.5 Hz, 3H), 3.73 (s, 3H), 4.15 (d, J = 10 Hz, 1H), 4.31 (d, J = 10 Hz, 1H), 4.41 (q, J = 7.5 Hz, 1H), 6.79 (d, J = 7.5 Hz, 2H), 7.15−7.31 (m, 7H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.2, 55.3, 69.9, 77.2, 113.7, 126.1, 127.4, 128.1, 128.5, 130.7, 143.8, 160.4. MS: m/z 242 (41, M+). Anal. Calcd for C16H18O2 (242.31): C, 79.31; H, 7.49. Found: C, 79.25; H, 7.41. 1-Fluoro-4-((1-phenylethoxy)methyl)benzene (3d). Colorless oil, Rf (n-hexane/EtOAc 10:2) = 0.49. Yield: 76% (185 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.32 (d, J = 7.5 Hz, 3H), 4.11 (d, J = 10 Hz, 1H), 4.23 (d, J = 12.5 Hz, 1H), 4.34 (q, J = 7.5 Hz, 1H), 6.85 (t, J = 7.5 Hz, 2H), 7.10−7.23 (m, 7H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.9, 69.6, 77.3, 115.1 (d, 2JCF = 21.25 Hz), 126.3, 127.6, 128.5, 129.4 (d, 3JCF = 8.12 Hz), 134.3 (d, 4JCF = 2.50 Hz), 143.5, 162.2 (1JCF = 243.75 Hz). MS: m/z 230 (28, M+). Anal. Calcd for C15H15FO (230.27): C, 78.24; H, 6.57. Found: C, 78.18; H, 6.50. 1-((1-Phenylethoxy)methyl)-4-(trifluoromethyl)benzene (3e). Creamy white oil, Rf (n-hexane/EtOAc 10:3) = 0.46. Yield: 72% (202 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.32 (d, J =

aldehydes and found that benzaldehyde underwent the etherification in the presence of butyraldehyde. Next, the experiment was performed between allylic and benzylic substrates, which led to the selective coupling of the benzylic substrate to furnish the ether 3d in 76% yield. It seems that the allyl substrate forms a stable complex with Ni so that it can not react further to produce the desired product.25 Finally, in a competing experiment between the benzylic substrates and tertbutanol as an aliphatic alcohol, we exclusively observed that tert-butanol cannot form ether under the optimized conditions. This observation refers to the mechanistic aspect of the process, representing the existence of a η3-bond nickel complex.16 In another experiment, the (benzyloxy)benzene was used instead of TBT, and the reaction failed to proceed (Scheme 6). Scheme 6. Role of Triazine Ring in Activation of C−O Bond and Accomplish of Reaction

This experiment revealed that the triazine ring has an important role in the activation of benzyl alcohols, which may be referred to the C−O bond activation function, and coordination of a nitrogen atom to facilitate the Ni-catalyzed C−O bond cleavage.26 It should be mentioned that the residue of the reaction mixture after completion is cyanuric acid, which was recovered from the reaction mixture.27 Also, in the absence of MgCl2, the reaction yield was decreased significantly. This experiment shows that MgCl2 plays a key role in stabilization of the active organometallic species during the reaction progress.28 In conclusion, we established a new and selective method for the reaction of benzylic electrophiles with aldehydes using a Nicatalyzed process. For primary substrates, the alcoholic products were obtained via C−C coupling reactions, while for secondary and tertiary substrates the preferred product is ether through the C−O bond formation reaction. The TCT reagent was used to activate the C−O bond of benzyl alcohols to undergo the coupling reaction with aldehydes as benzyl C− O electrophiles. Ethylene glycol was used as a green solvent and also as a reducing agent to accomplish the reaction under more environmentally friendly conditions. This nickel-catalyzed process opened up a new way for synthesis of bulky substituted benzyl ethers and benzyl alcohols, which could find a high potential application in organic synthesis.

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EXPERIMENTAL SECTION

General. All of the commercial reagents and solvents were used without further purification. Melting points were determined in open capillary tubes. FT-IR spectroscopy was employed for characterization of the synthesized compounds using film KBr pellet techniques. NMR spectra were acquired in DMSO-d6 with tetramethylsilane (TMS) as the internal standard. The sample was analyzed by GC/MS for mass spectrometry and a microanalyzer for elemental analyses. Reaction monitoring was accomplished by TLC on silica gel plates. Column chromatography was carried out on columns of silica gel 60 (70−230 mesh). General Procedure for the Ni-Catalyzed Addition of Benzyl Alcohols to Aldehydes Using TCT Reagent. In a flask (50 mL), a mixture of benzyl alcohol (1.0 mmol) and NaH (1.2 mmol) was 977

DOI: 10.1021/acs.joc.7b02281 J. Org. Chem. 2018, 83, 973−979

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The Journal of Organic Chemistry

TMS): δ (ppm) 24.1, 33.8, 55.1, 65.3, 86.2, 113.1, 126.3, 126.7, 127.0, 127.8, 128.2, 130.1, 136.3, 136.6, 145.2, 147.6, 158.4. MS: m/z 452 (27, M+). Anal. Calcd for C31H32O3 (452.58): C, 82.27; H, 7.13. Found: C, 82.18; H, 7.05. 4,4′-(((4-Methoxybenzyl)oxy)(phenyl)methylene)bis(methoxybenzene) (3n). Brown oil, Rf (n-hexane/EtOAc 10:4) = 0.33. Yield: 60% (264 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 3.71 (s, 6H), 3.81 (s, 3H), 4.01 (s, 2H), 6.74−6.83 (m, 6H), 6.89 (d, J = 10 Hz, 2H), 7.32 (d, J = 10 Hz, 4H), 7.39−7.53 (m, 5H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 55.5, 65.2, 86.4, 113.1, 113.14, 126.7, 128.4, 129.1, 129.4, 129.7, 130.1, 136.4, 143.7, 158.4, 160.1. MS: m/z 440 (25, M+). Anal. Calcd for C29H28O4 (440.53): C, 79.07; H, 6.41. Found: C, 79.01; H, 6.33. 4,4′-(Phenyl((4-(trifluoromethyl)benzyl)oxy)methylene)bis(methoxybenzene) (3o). Creamy yellow oil, Rf (n-hexane/EtOAc 10:4) = 0.30. Yield: 60% (287 mg). 1H NMR (250 MHz, CDCl3/ TMS): δ (ppm) 3.63 (s, 6H), 4.13 (s, 2H), 6.71 (d, J = 7.5 Hz, 4H), 7.05−7.20 (m, 3H), 7.28 (d, J = 10 Hz, 4H), 7.35−7.48 (m, 6H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 55.1, 64.9, 86.6, 113.2, 122.1, 125.1 (q, 3JCF = 3.75 Hz), 126.9, 127.9, 128.0, 128.8, 129.3, 130.0, 135.9, 143.5, 144.8, 158.6. MS: m/z 478 (18, M+). Anal. Calcd for C29H25F3O3 (478.50): C, 72.79; H, 5.27. Found: C, 72.70; H, 5.17. 1-(4-(Methylthio)phenyl)-2-phenylethanol (4a). Light brown oil, Rf (n-hexane/EtOAc 10:2) = 0.47. Yield: 86% (210 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.97 (s, 1H), 2.40 (brs, 2H), 2.89−2.92 (m, 3H), 4.74−4.79 (m, 1H), 7.08−7.22 (m, 9H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 38.5, 46.1, 75.6, 128.4, 128.6, 131.96, 132.0, 132.1, 136.2, 137.0, 137.1. MS: m/z 244 (32, M +). Anal. Calcd for C15H16OS (244.35): C, 73.73; H, 6.60. Found: C, 73.64; H, 6.52. 1-(2-Methoxyphenyl)-2-(4-methoxyphenyl)ethanol (4b). Light yellow oil, Rf (n-hexane/EtOAc 10:5) = 0.42. Yield: 78% (201 mg). 1 H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.25 (s, 1H), 2.89−2.96 (m, 2H), 3.81−3.87 (m, 6H), 5.04 (s, 1H), 6.73−6.96 (m, 4H), 7.14− 7.26 (m, 4H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 43.2, 55.2, 55.5, 73.8, 110.2, 113.7, 120.4, 128.3, 128.5, 130.4, 130.7, 132.3, 156.9, 158.4. MS: m/z 258 (19, M+). Anal. Calcd for C16H18O3 (258.31): C, 74.39; H, 7.02. Found: C, 74.31; H, 6.97. 5-(1-Hydroxy-2-(4-isopropylphenyl)ethyl)-2-methoxyphenol (4c). Colorless oil, Rf (n-hexane/EtOAc 10:5) = 0.37. Yield: 81% (232 mg). 1 H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.23−1.26 (m, 6H), 1.59 (s, 1H), 2.25 (s, 1H), 2.44−2.64 (m, 1H), 2.90 (s, 1H), 3.89 (s, 3H), 4.71 (s, 1H), 4.83 (s, 1H), 6.98 (d, J = 10 Hz, 1H), 7.01−7.14 (m, 2H), 7.21−7.31 (m, 4H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.0, 35.7, 45.0, 56.7, 74.8, 113.3, 115.6, 119.8, 126.6, 127.6, 134.7, 136.0, 145.1, 145.9, 150.4. MS: m/z 286 (30, M+). Anal. Calcd for C18H22O3 (286.37) C, 75.50; H, 7.74. Found: C, 75.44; H, 7.68. 4-(2-Hydroxypentyl)benzonitrile (4d). Pale yellow oil, Rf (nhexane/EtOAc 10:3) = 0.40. Yield: 68% (129 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 0.84−0.88 (m, 3H), 1.53−1.60 (m, 4H), 1.99 (s, 1H), 2.89−2.91 (m, 2H), 4.77 (s, 1H), 7.41 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/ TMS): δ (ppm) 13.7, 18.5, 36.5, 44.8, 71.6, 105.6, 118.3, 127.7, 128.9, 145.8. MS: m/z 189 (71, M+). Anal. Calcd for C12H15NO (189.25): C, 76.16; H, 7.99; N, 7.40. Found: C, 76.11; H, 7.92; N, 7.33. 1-(4-(Dimethylamino)phenyl)-2-(4-nitrophenyl)ethanol (4e). Yellow oil, Rf (n-hexane/EtOAc 10:3) = 0.34. Yield: 88% (252 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.18 (s, 1H), 2.77−3.01 (m, 8H), 4.73−4.79 (m, 1H), 6.61−6.68 (m, 2H), 7.07−7.09 (m, 2H), 7.65−7.72 (m, 2H), 8.04−8.08 (m, 2H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 40.1, 72.9, 111.6, 120.9, 123.6, 129.1, 130.5, 145.6, 148.0, 150.2. MS: m/z 286 (44, M+). Anal. Calcd for C16H18N2O3 (286.33): C, 67.12; H, 6.34; N, 9.78. Found: C, 67.19; H, 6.37; N, 9.85. 2-(4-Nitrophenyl)-1-(thiophen-2-yl)ethanol (4f). Yellow oil, Rf (nhexane/EtOAc 10:3) = 0.33. Yield: 79% (197 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.18 (s, 1H), 3.00 (s, 2H), 5.13 (t, J = 7.5 Hz, 1H), 7.15−7.30 (m, 4H), 7.44−7.48 (d, J = 10 Hz, 1H), 8.06 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 40.2, 69.1, 120.9, 123.6, 125.5, 127.2, 129.1, 143.3, 145.6, 148.0. MS:

7.5 Hz, 3H), 4.11 (d, J = 10 Hz, 1H), 4.23 (d, J = 12.5 Hz, 1H), 4.34 (q, J = 7.5 Hz, 1H), 7.11−7.24 (m, 7H), 7.55 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.3, 69.6, 77.5, 122.1, 125.1 (q, 3JCF = 3.75 Hz), 126.9, 127.9, 128.0, 130.0, 135.9, 143.4, 144.9. MS: m/z 280 (33, M+). Anal. Calcd for C16H15F3O (280.28): C, 68.56; H, 5.39. Found: C, 68.50; H, 5.31. 4-((1-Phenylethoxy)methyl)benzonitrile (3f). Colorless oil, Rf (nhexane/EtOAc 10:3) = 0.43. Yield: 70% (166 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.43 (d, J = 7.5 Hz, 3H), 4.26−4.36 (m, 2H), 4.43 (q, J = 7.5 Hz, 1H), 7.26−7.36 (m, 5H), 7.43 (d, J = 10 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.3, 69.6, 77.4, 112.5, 118.6, 126.4, 127.9, 128.8, 129.4, 132.7, 142.6, 144.5. MS: m/z 237 (19, M+). Anal. Calcd for C16H15NO (237.29): C, 80.98; H, 6.37; N, 5.90. Found: C, 80.90; H, 6.30; N, 5.84. 1-Nitro-4-((1-phenylethoxy)methyl)benzene (3g). Yellow oil, Rf (n-hexane/EtOAc 10:3) = 0.41. Yield: 70% (180 mg). 1H NMR (400 MHz, CDCl3/TMS): δ (ppm) 1.42 (d, J = 8.0 Hz, 3H), 4.64 (d, J = 12.0 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.82 (q, J = 8.0 Hz, 1H), 7.22−7.30 (m, 5H), 7.44 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl3/TMS): δ (ppm) 25.1, 63.9, 70.5, 123.7, 125.4, 127.0, 127.5, 128.5, 143.1, 145.5, 148.9. MS: m/z 257 (35, M+). Anal. Calcd for C15H15NO3 (257.28): C, 70.02; H, 5.88; N, 5.44. Found: C, 69.93; H, 5.81; N, 5.35. ((Benzyloxy)methanetriyl)tribenzene (3h). Light yellow oil, Rf (nhexane/EtOAc 10:2) = 0.57. Yield: 68% (238 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 4.08 (s, 2H), 6.99−7.31 (m, 14H), 7.42 (d, J = 7.5 Hz, 6H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 65.8, 87.0, 127.1, 127.4, 127.9, 128.3, 128.8, 129.6, 139.2, 144.2. MS: m/z 350 (17, M+). Anal. Calcd for C26H22O (350.45): C, 89.11; H, 6.33. Found: C, 89.02; H, 6.25. (((4-Isopropylbenzyl)oxy)methanetriyl)tribenzene (3i). Dark brown oil, Rf (n-hexane/EtOAc 10:2) = 0.55. Yield: 65% (255 mg). 1 H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.16 (d, J = 7.5 Hz, 6H), 2.73−2.89 (m, 1H), 4.05 (s, 2H), 7.09−7.24 (m, 13H), 7.42 (d, J = 7.5 Hz, 6H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 24.1, 33.9, 65.6, 86.9, 125.9, 127.3, 127.9, 128.8, 129.6, 136.5, 144.2, 147.8. MS: m/z 392 (23, M+). Anal. Calcd for C29H28O (392.53): C, 88.73; H, 7.19. Found: C, 88.65; H, 7.10. (((4-Methoxybenzyl)oxy)methanetriyl)tribenzene (3j). White solid, Rf (n-hexane/EtOAc 10:3) = 0.48. Yield: 64% (243 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 3.70 (s, 3H), 4.01 (s, 2H), 6.79 (d, J = 7.5 Hz, 2H), 7.11−7.24 (m, 11H), 7.42 (d, J = 7.5 Hz,6H). 13 C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 55.3, 65.4, 86.9, 113.7, 127.0, 127.2, 128.5, 128.7, 131.2, 144.2, 158.8. MS: m/z 380 (16, M+). Anal. Calcd for C27H24O2 (380.48): C, 85.23; H, 6.36. Found: C, 85.16; H, 6.14. (((4-(Trifluoromethyl)benzyl)oxy)methanetriyl)tribenzene (3k). Creamy yellow oil, Rf (n-hexane/EtOAc 10:2) = 0.41. Yield: 61% (255 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 4.19 (s, 2H), 6.92 (d, J = 7.5 Hz, 2H), 7.14 (t, J = 7.5 Hz, 3H), 7.26 (t, J = 7.5 Hz, 6H), 7.39 (d, J = 7.5 Hz, 6H), 7.67 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 64.9, 86.3, 122.7, 125.1 (q, 3JCF = 3.75 Hz), 126.9, 127.9, 129.3, 130.0, 135.1, 142.9, 144.8. MS: m/z 418 (14, M+). Anal. Calcd for C27H21F3O (418.45): C, 77.50; H, 5.06. Found: C, 77.42; H, 5.00. 4,4′-((Benzyloxy)(phenyl)methylene)bis(methoxybenzene) (3l). Creamy white solid, Rf (n-hexane/EtOAc 10:4) = 0.37. Yield: 63% (258 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 3.63 (s, 6H), 4.07 (s, 2H), 6.72 (d, J = 10 Hz, 4H), 7.05−7.32 (m, 12H), 7.41 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 55.2, 65.6, 86.4, 113.2, 126.8, 127.0, 127.1, 127.9, 128.2, 128.3, 130.1, 136.4, 139.3, 145.2, 158.5. MS: m/z 410 (11, M+). Anal. Calcd for C28H26O3 (410.50): C, 81.92; H, 6.38. Found: C, 81.85; H, 6.31. 4 ,4′ -(((4 -Iso propylb enzyl)oxy)( phenyl)methylene)bis (methoxybenzene) (3m). Light yellow oil, Rf (n-hexane/EtOAc 10:4) = 0.35. Yield: 62% (280 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.14 (d, J = 7.5 Hz, 6H), 2.67−2.85 (m, 1H), 3.64 (s, 6H), 4.04 (s, 2H), 7.72 (d, J = 10 Hz, 4H), 7.08−7.23 (m, 7H), 7.31 (d, J = 10 Hz, 4H), 7.42 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/ 978

DOI: 10.1021/acs.joc.7b02281 J. Org. Chem. 2018, 83, 973−979

Note

The Journal of Organic Chemistry m/z 249 (37, M+). Anal. Calcd for C12H11NO3S (249.29): C, 57.82; H, 4.45; N, 5.62. Found: C, 57.75; H, 4.41; N, 5.54. 2-(Furan-2-yl)-1-(thiophen-2-yl)ethanol (4g). Colorless oil, Rf (nhexane/EtOAc 10:2) = 0.47. Yield: 70% (136 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 2.00 (s, 1H), 3.50−3.51 (m, 1H), 3.56−3.58 (m, 1H), 4.97 (s, 1H), 6.73−6.94 (m, 5H), 7.15−7.18 (m, 1H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 45.0, 76.2, 105.9, 109.4, 124.6, 126.6, 126.9, 141.6, 143.5, 155.2. MS: m/z 194 (63, M+). Anal. Calcd for C10H10O2S (194.25): C, 61.83; H, 5.19; S, 16.51, Found: C, 61.75; H, 5.12; S, 16.44. 1-(4-Chlorophenyl)-2-(4-fluorophenyl)ethanol (4h). Pale yellow oil, Rf (n-hexane/EtOAc 10:3) = 0.45. Yield: 87% (218 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.94 (s, 1H), 2.75 (s, 1H), 2.83 (s, 1H), 4.52 (s, 1H), 6.88−6.98 (m, 2H), 7.07−7.24 (m, 6H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 36.6, 64.2, 115.4, 128.1, 128.5, 129.8, 133.1, 134.5, 139.5, 160.9, 162.7. MS: m/z 250 (29, M+). Anal. Calcd for C14H12ClFO (250.70): C, 67.07; H, 4.82. Found: C, 66.95; H, 4.74. 4-(1-Hydroxy-2-mesitylethyl)benzonitrile (4i). Colorless oil, Rf (nhexane/EtOAc 10:3) = 0.38. Yield: 74% (196 mg). 1H NMR (250 MHz, CDCl3/TMS): δ (ppm) 1.98 (s, 1H), 2.23−2.26 (m, 9H), 2.82 (s, 1H), 2.90 (s, 1H), 4.93 (s, 1H), 6.82 (s, 2H), 7.14 (d, J = 10 Hz, 2H), 7.48 (d, J = 7.5 Hz, 2H). 13C NMR (62.5 MHz, CDCl3/TMS): δ (ppm) 20.9, 21.3, 40.9, 74.0, 108.6, 119.4, 125.5, 128.1, 130.1, 132.1, 139.0, 147.9, 159.8. MS: m/z 265 (25, M+). Anal. Calcd for C18H19NO (265.35): C, 81.47; H, 7.22; N, 5.28. Found: C, 81.40; H, 7.14; N, 5.20.

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(6) Kim, J.; Lee, D.-H.; Kalutharage, N.; Yi, C. S. ACS Catal. 2014, 4, 3881. (7) Thompson, S. J.; Thach, D. Q.; Dong, G. J. Am. Chem. Soc. 2015, 137, 11586. (8) (a) Sassaman, M. B.; Kotian, K. D.; Surya Prakash, G. K.; Olah, G. A. J. Org. Chem. 1987, 52, 4314. (b) Chandrasekhar, S.; Chandrashekar, G.; NagendraBabu, B.; Vijeender, K.; Venkatram Reddy, K. Tetrahedron Lett. 2004, 45, 5497. (9) Hatakeyama, S.; Mori, H.; Kitano, K.; Yamada, H.; Nishizawa, M. Tetrahedron Lett. 1994, 35, 4367. (10) (a) Yang, W.-C.; Lu, X.-A.; Kulkarni, S. S.; Hung, S.-C. Tetrahedron Lett. 2003, 44, 7837. (b) Iwanami, K.; Seo, H.; Tobita, Y.; Oniyama, T. Synthesis 2005, 183. (11) Kalutharage, N.; Yi, C. S. Org. Lett. 2015, 17, 1778. (12) (a) Lee, S. H.; Park, Y. J.; Yoon, C. M. Tetrahedron Lett. 1999, 40, 6049. (b) Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. J. Am. Chem. Soc. 2003, 125, 11456. (13) Pan, M.; Brush, A. J.; Dong, G.; Mullins, C. B. J. Phys. Chem. Lett. 2012, 3, 2512. (14) Milone, C.; Trapani, M. C.; Galvagno, S. Appl. Catal., A 2008, 337, 163. (15) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2010, 49, 4993. (16) Panahi, F.; Bahmani, M.; Iranpoor, N. Adv. Synth. Catal. 2015, 357, 1211. (17) Panahi, F.; Jamedi, F.; Iranpoor, N. Eur. J. Org. Chem. 2016, 2016, 780. (18) Skrabalak, S. E.; Wiley, B. J.; Kim, M.; Formo, E. V.; Xia, Y. Nano Lett. 2008, 8, 2077. (19) Díaz-Á lvarez, A. E.; Cadierno, V. Appl. Sci. 2013, 3, 55. (20) Luo, C.; Zhang, Y.; Zeng, X.; Zeng, Y.; Wang, Y. J. Colloid Interface Sci. 2005, 288, 444. (21) See the Supporting Information. (22) Srinivas, K.; Sitha, S.; Rao, V. J.; Bhanuprakash, K.; Ravikumar, K. J. Mater. Chem. 2006, 16, 496. (23) (a) Yamada, K.; Fujita, H.; Kunishima, M. Org. Lett. 2012, 14, 5026. (b) Cao, Z.-C.; Luo, F.-X.; Shi, W.-J.; Shi, Z.-J. Org. Chem. Front. 2015, 2, 1505. (24) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; Vol. 76. (25) Taube, R.; Schmidt, U.; Gehrke, J.-P.; Böhme, P.; Langlotz, J.; Wache, S. Makromol. Chem., Macromol. Symp. 1993, 66, 245. (26) Peng, Z.; Yu, Z.; Li, T.; Li, N.; Wang, Y.; Song, L.; Jiang, C. Organometallics 2017, 36, 2826. (27) Fujita, H.; Hayakawa, N.; Kunishima, M. J. Org. Chem. 2015, 80, 11200. (28) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 4665.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02281. Copies of 1H and 13C for all synthesized compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Farhad Panahi: 0000-0003-0420-4409 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the research councils of Shiraz University and a grant from the Iran National Elite Foundation are gratefully acknowledged.

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REFERENCES

(1) Krti, L.; Czak, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier: Burlington, MA, 2005; pp 484 − 485. (2) Cuenca, C A. B.; Mancha, G.; Asensio, G.; Medio-Simon, M. Chem. - Eur. J. 2008, 14, 1518. (3) (a) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043. (b) Pitsinos, E. N.; Vidali, V. P.; Couladouros, E. A. Eur. J. Org. Chem. 2011, 2011, 1207. (c) Heintz, A.; Kapteina, S.; Verevkin, S. P. J. Phys. Chem. B 2007, 111, 10975. (d) Nelson, S. G.; Wang, K. J. Am. Chem. Soc. 2006, 128, 4232. (4) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P. Chem. Rev. 2009, 109, 2551. (5) Haibach, M. C.; Guan, C.; Wang, D. Y.; Li, B.; Lease, N.; Steffens, A. M.; Krogh-Jespersen, K.; Goldman, A. S. J. Am. Chem. Soc. 2013, 135, 15062. 979

DOI: 10.1021/acs.joc.7b02281 J. Org. Chem. 2018, 83, 973−979