BF 3 · OEt 2-Mediated Benzylation of Arenes and Heteroarenes with Benzyl Ether Derivatives

An efficient BF3·Et2O-promoted benzylation of arenes and heteroarenes with various benzyl ether derivatives has been developed. This method provided alternative access to valuable diarylmethane in good yields under mild conditions via an easy work-up procedure.

Recently, we have focused our attention on Lewis acidcatalyzed N-alkylation of sulfonamides using unactive ethers as alkyalting agents.During the period that we investigated the effect of various Lewis acids on the Nalkylation of 4-toluene sulfonamide 5 in toluene solvent, we found BF 3 •Et 2 O could enhance the formation of byproduct diarylmethane 3a and 4a (around 10% yield) from the alkyaltion of toluene 2a and benzyl ether 1a (see Scheme 1), and further studies indicated that byproduct diarylmethane 3a and 4a did not form in the presence of other Lewis acids including AlCl 3 , TiCl

Results and Discussions
Initially, the alkylation of toluene with dibenzyl ether was employed as a model reaction, optimization studies were carried out under different conditions, and the corresponding results were summarized in Table 1.As shown in Table 1, when the FCA of toulene (6.0 equiv.)with dibenzyl ether (0.5 mmol) was carried out using BF 3 •Et 2 O (3.0 equiv.)as promoter under refluxing condition in Scheme 1. Lewis acid-poromoted N-alkylation of sulfonamide and alkylation of toluene.a Unless otherwise noted, all the reactions were carried out under Ar atmosphere in sealed tube, benzyl ethers (0. different solvents (1.5 mL) for 24 h, we found the nature of solvents had significant effect on this transformation (entries 1 -9), among the solvents examined, 1,4-dioxane gave the best result (68% yield) (entry 8).The further optimized results indicated that the suitable substrate ratio (2a/1a = 12) could lead to the best yield (75%) (compare entries 8, 10 and11), and lowering the reaction temperature to 90˚C or increasing to 140˚C resulted in a decreased yield due to incomplete reaction or tedious work-up, respectively (compare entries 10, 12 and 14).Finally, we investigated the effect of BF 3 •Et 2 O loading on the transformation, and found a decreased yield of diarylmethane was obtained at low promoter loading (2.0 equiv.)(compare entries 10 and 15), but higher promoter loading (5.0 equiv.)did not increase the yield of desired compound any further (compare etnries 10 and 16).
With the optimized parameters in hand, we tested the general applicability of the BF 3 •Et 2 O-promoted FCA of arene with dibenzyl ether, by varying both the ether and the arene/heteroarene.As shown in Table 2, the benzyl ether alkylating reagents examined could be performed smoothly in moderate to good yields.Analysis of the efficiency about this transformation indicates that electronic effect gorven the FCA system.The alkyaltion of dibenzyl ether with electron-rich aromatic compounds containing methyl, methoxy or hydroxyl group could occur 53 e (7:10) a Unless otherwise noted, all reactions were carried out in sealed tube at 110˚C under Ar atmosphere for 24 h, benzyl ethers (0.5 mmol), arenes (12.0 equiv), BF 3 .Et 2 O (3.0 equiv), 1, 4-dioxane used as solvent (1.5 mL ); b All products are known compounds and identified using 1 H NMR, LR-MS and IR; c Isolated yield and the ratio of the isomers were determined by 1 H NMR; d Reaction temp.: 60˚C, reaction time: 36 h; e Reactiom temp.: 150˚C, reaction time: 42 h.efficiently to afford diarylmethan in moderate to good yield (entries 1 -6).On the contray, benzyl ether derivates with an electon-withdrawing group such as nitro gave lower yield of the corresponding alkyalted products (compare entries 1 and 17).Even worse, if arenes had a chloride or nitro group, the FCA did not occur at all (entries 7 and 8).It is worth to note that BF 3 .Et 2 O could also efficiently promote the benzylation of heteroarenes such as thiophene and furan to give corresponding diheteroaryl-methane (entries 11 and 12), but we found that the arene substrates containing oxygen hetero-atom gave low yield (17% -49%) of alkyalted product (entries 6, 10 and 12), this is possibly due to that the coordination of the ether oxygen or phenolic oxygen with B(III) decreased the electron density in the arene ring, and resulted in poor reactivity.It is more interesting that oxygen heteroatomcontaining substrates such as 2f, 2j and 2l gave poor yields of benzylated products, but better regioselectivity was observed (compare entries 1 and 6, 10 and 12), especially for substrate 2j, 100% regioselectivity was achieved (entry 10).

Conclusions
In conclusion, we have demonstrated a BF 3 •Et 2 O-mediated benzylation of arenes and heteroarenes using benzyl ethers as the alkylating agents.Various ethers, arenes and heteroarenes were systematically studied, and low reactivity of oxygen-hetero atom-containging arenes was also observed.This method used inexpensive and comercially available BF 3 •Et 2 O as promoter, and provided complementary access to valuable diarylmethane under mild conditions.

General Experimental Information
Unless otherwise noted, all experiments were performed under Ar atmosphere in a sealed tube.All reagents were purchased from TCI, Acros or strem.Solvents were treated with 4Å molecular sieves or sodium and distilled prior to use.Purifications of reaction products were car-ried out by flash chromatography using silica gel (40 -63 mm) from Qingdao Haiyang Chemical Co. Ltd.Infrared spectra (IR) were recorded on a Brucker TENSOR 27 FTIR spectrophotometer and are reported as wavelength numbers (cm -1 ). 1 H NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer.Chemical shifts are reported in parts per million (ppm) and coupling constants are reported as Hertz (Hz).Splitting patterns are designated as singlet (s), broad singlet (bs), doublet (d), triplet (t).Splitting patterns that could not be interpreted or easily visualized are designated as multiplet (m).Low resolution mass spectra were recorded using GC-MS.

General Procedure
Benzyl ether derivatives (0.5 mmol), arenes or heteroarenes (6.0 mmol), BF 3 .OEt 2 (3.0 equiv, 1.5 mmol) and 1, 4-dioxane (1.5 mL) were combined in a pressure tube equipped with a stir bar, The mixture was heated to given temperature and stirred for the given time under Ar atmosphere.When the starting material has disappeared (monitored by TLC), the reaction mixture was treated with 10.0 mL of H 2 O, filtrated and the corresponding filtrate was extracted with ethyl acetate (3 × 15 mL), the combined organic layers were concentrated, and the residue was purified by flash column chromatography (silica gel) to furnish target product.All products are known compounds and identified using 1 H NMR, LRMS and IR by comparison with previously reported data.