(Aryl)(2-furyl)alkanes and their derivatives, 20. 1 Synthesis of symmetric bis-and tris(2-furyl)methanes

New methods for the synthesis of symmetric 5,5’-disubstituted bis-and 5,5’,5”-trisubstituted tris(2-furyl)methanes have been developed. Symmetric bis(2-furyl)methanes were prepared from 5-substituted 2-furylmethanols in the presence of concentrated perchloric acid. The attempted synthesis of (aryl)[bis(2-furyl)]methanes from (aryl)(2-furyl)methanols in the presence of acid catalysts failed. The reaction of 5-substituted 2-furaldehydes with ethylene glycol in the presence of strong acid catalysts led to tris(2-furyl)methanes. Plausible mechanisms of these transformations are discussed.


Introduction
3][4][5] However, the synthesis of symmetric bis(2-furyl)methanes is still an important and challenging goal.The availability of these compounds continues to be of interest because they are industrially important.7][8][9] Our research in the area of the chemistry of (aryl)(2-furyl)methanes led us to elaborate convenient routes to derivatives of bis-and tris(2-furyl)methanes. 10is(2-furyl)methanes.The self-condensation of furfuryl alcohols is a useful and interesting method for the synthesis of symmetric bis(2-furyl)methanes.The acid-promoted oligomerization of furfuryl alcohol gives a mixture of products, among those bis(2-furyl)methane has been isolated in low yield. 11It has been also found that the reaction of (5-aminomethyl-2-furyl)methanol with 5.1 M hydrochloric ISSN 1551-7004 Page 642  ARKAT USA, Inc acid furnished bis(5-aminomethyl-2-furyl)methane as a minor product. 12Hydrothermolysis of (5methyl-2-furyl)methanol at 300 ºC and pH ~ 7 produced bis(5-methyl-2-furyl)methane in 15% yield. 13All these formations of bis(2-furyl)alkanes occur as side reactions, and the low yields make these reactions less important for synthetic purposes.On the other hand, there are also reports of excellent yields for the preparation of bis(2-furyl)alkanes from 3-, 5-alkyl-, and 3,5dialkyl-substituted 2-furylalkanols (Scheme 1).These reactions proceed in the presence of polyphosphoric acid, 14 silver(I) ions or trichloroacetic acid. 15Some bis(5-aryl-2-furyl)methanes have been reported to show tuberculostatic activity, but these compounds were obtained only as by-products of some reactions. 16Therefore, the search for new approaches and better reaction conditions for the preparation of symmetric bis(2-furyl)methanes remains an interesting task.

Results and Discussion
We have tried to develop a simple and efficient synthetic approach to symmetric bis(2furyl)alkanes based on the self-condensation of 2-furylmethanols under acidic conditions.As starting materials (5-aryl-2-furyl)methanols (1) were chosen, and we found that these alcohols in dioxane solution and in the presence of perchloric acid were transformed into bis(5-aryl-2furyl)methanes (2) (Scheme 2).

Scheme 3
An analogous conversion of hetarylmethanols into bis(hetaryl)methanes has been described earlier by Balaban and co-workers 14 for furan derivatives and by Jackson et al. for 2pyrrolylmethanoles. 17,18 Two conceivable pathways, Path a or Path b (as outlined in Scheme 4) may explain the formation of bis(2-furyl)alkanes from 2-furylmethanols. 14,15SSN 1551-7004 Page 644

Scheme 4
We could not find any report in the literature on the formation of aryl[bis(2-furyl)]methanes emerging from a self-condensation of aryl(2-furyl)methanols under acidic reaction conditions.It was anticipated (cf.Scheme 4) that protonation of aryl(5-methyl-2-furyl)methanol (5) would give rise to an aryl(2-furyl)methyl cation A (R = aryl, R 1 = methyl); a conceivable alternative would be protonation at the 2-position of the furan ring forming the cation intermediate B (R = aryl, R 1 = methyl), which, in turn, may undergo loss of araldehyde and after deprotonation provides the 2-methylfuran C as an intermediate.Conceivably, following either Path a or Path b aryl[bis(2furyl)]methanes 6 may be formed.However, all attempts to convert aryl(5-methyl-2furyl)methanols (5a-c) [For a X = H; b X = CH3; c = OCH3] with the aid of various acid catalyst [HClO4, TsOH, BF3•Et2O, Amberlyst 15, KU-2, HCl (gas), H2SO4] into aryl[bis(2furyl)]methanes 6a-c failed.Treatment of 5a-c with acid catalysts in benzene or dioxane solutions resulted only in tar production (possibly via the cation intermediate D after deprotonation of the presumed first-formed intermediate A (Scheme 5).However, when (5methyl-2-furyl)phenylmethanol (5a) was treated with hydrochloric acid in ethanol solution the corresponding ethyl ether 7a was obtained, and this is taken as evidence of the intermediacy of cation A.

Scheme 6
After separation of the salt 9b + ClO4 -from the reaction of 8b with trityl perchlorate traces of tris(5-methyl-2-furyl)methane 9b were detected by GLC. 22We suppose that 9b was formed from Page 646  ARKAT USA, Inc dioxolane 8b upon reaction with an electrophilic reagent such as trityl perchlorate or by perchloric acid (presumably, the latter may have been generated by the hydrolysis of trityl perchlorate induced by moisture from air or from the solvent used) according to Scheme 10 (vide infra).For the conversion of 8b into 9b, HClO4 provides H + ; alternatively, if Tr + ClO4 -is the electrophilic reagent (H + is replaced by Tr + , and in this case, OH of the subsequent intermediates [in Scheme 10 their structures are placed in brackets] is to be exchanged by OTr).An analogous conversion was described by Clezy et al. 23 These authors have discovered that the reaction of ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate with ethylene glycol in the presence of TsOH as catalyst led to the formation of a tris(1H-2-pyrrolyl)methane derivative instead of the expected acetal of the 1H-pyrrole-2-carbaldehyde (Scheme 7).

Scheme 7
As West et al. 24 have found, the treatment of 2-acylfurans with 1,2-diols in the presence of one molar equivalent of TsOH•H2O does not furnish the desired ketal products.Instead, the isolated products were 1-O-acyl-2-O-(4-toluenesulfonyl) derivatives of the 1,2-diol reactants.The authors explain the formation of these products as the result of the protonation of the first-formed ketal intermediate, a 2-(2-furyl) [1,3]dioxolane derivative.Protonation of the furan moiety of this intermediate is presumed to be followed by the formation of furan and a [1,3]dioxolan-2-ylium cation.The latter intermediate reacts with tosylate under ring-opening to give the isolated ester (Scheme 8).For this process the name "protiodefuranation" has been coined. 24SSN 1551-7004 Page 647 TsO -

Scheme 8
With these literature reports in mind we tried to develop an efficient and simple route to symmetric 5,5',5"-trisubstituted tris(2-furyl)methanes 9.For this purpose we studied the influence of various acids as catalysts on the reaction of 5-methyl-2-furylaldehyde (10b) and ethylene glycol. 22Both 2-(5-methyl-2-furyl) [1,3]dioxolane (8b) and tris(5-methyl-2furyl)methane (9b) were formed (Scheme 9).The product ratio varied depending on the catalyst employed as was revealed by monitoring the reaction mixture by GLC: The weakly acidic KU-2 resin gave rise to mainly 8b and only traces of 9b; with the ion-exchanging resin Amberlyst 15 the ratio 8b 9b depended of the amount of the catalyst employed: 10 mol% catalyst yielded a twenty-fold excess of 8b over 9b, whereas with 50 mol% catalyst the ratio was reversed, and only traces of 8b were formed beside the main product 9b.Similarly, boron trifluoride etherate furnished mainly 9b and only traces of 8b.With p-toluenesulfonic acid and perchloric acid the selectivity was less pronounced and the ratio 8b : 9b was found as 3 : 1 and 1 : 5, respectively.
The former products 2 were prepared from 5-substituted 2-furylmethanols 1 with concentrated perchloric acid.The latter products 9 arose from the reaction of 5-substituted 2-furaldehydes 10 with ethylene glycol in the presence of a strongly acidic catalysts.Notable advantages of the described methods are the simple and mild reaction conditions as well as good product yields.

Experimental Section
General Procedures.Melting points were determined on a Thomas capillary melting point apparatus. 1H NMR spectra were recorded on a Tesla BS 487 (80 MHz) and on a Bruker AMX-400 spectrometer (400 MHz).Gas chromatography (GLC) was performed with a Chrom-5 equipped with a flame ionization detector using a column (2500 x 3 mm) with 5% carbowax coated on Chromaton N-AW-DMCS; the carrier gas was nitrogen.Thin layer chromatography (TLC) was carried out on aluminium backed silica plates Silufol UV 254.Elemental analyses were carried out at this Laboratory.Compounds 1 were prepared by reduction of the corresponding 5-aryl-2-furaldehydes 10e-i with sodium borohydride. 272-Methylfuran 3 and the 5-substituted 2-furaldehydes 10b-d were commercial products.The following starting materials were prepared according to the procedure reported in the literature: 5, 28 8a,b, 25 8d, 29 5-aryl-2-furaldehydes 10a-i. 26The physical data of tris(5-methyl-2-furyl)methane 9b are in agreement with those given in lit. 19is(5-aryl-2-furyl)methanes (2a-e) General procedure.To a solution of (5-aryl-2-furyl)methanol (1a-e) (10 mmol) in dioxane (30-70 mL) was added HClO4 (70%, 0.5-1.0mL).As monitored by TLC the reaction was complete after 30-60 min.The reaction mixture was diluted with water (4-5 times the volume of the reaction mixture) and stirred until the separated oil turned crystalline.The precipitate formed was filtered off, washed with water, dried on air, and recrystallised from benzene-hexane mixtures after filtration of the hot solution through a layer of silica gel.
( 10-20 %Amberlyst 15 was added.The reaction mixture was kept at rt for 12-36 h or at reflux for 1-3 h.Thereafter, the reaction mixture was washed with NaHCO3 solution, water, and dried over Na2SO4.The solvent was completely evaporated, and residue was dissolved in benzene (2 mL) and analysed by GLC.No aryl(5-methyl-2-furyl)methanes 6a-c were detected using authentic samples 19 for comparison.

2-[(Ethoxy
)phenylmethyl]-5-methylfuran (7a).To a solution of (5-methyl-2furyl)phenylmethanol (5a) (1.88 g, 10 mmol) in ethanol (25 mL) hydrochloric acid (0.5 mL) was added.The reaction mixture was kept at rt for 4 h, diluted with water (100 mL) and extracted with dichloromethane (3 x 30 mL).The combined organic layers were washed with NaHCO3 solution, water, and dried over Na2SO4.The solvent was completely evaporated, and the residue was purified by column chromatography (silica gel, eluent hexane/chloroform 2:1); the main fraction afforded a pale yellow oil 7a (0.86 g, 40%).Most of the solvent was evaporated to reduce the volume to about 2 mL, and the residue was analyzed by GLC using authentic samples of 9b 19 and 8b. 25 The ratio of 8b : 9b was determined from the respective peak areas (cf.Results and Discussion section).
After the catalyst was filtered off, the solvent was evaporated in vacuo, and the residue was purified by column chromatography (on silica gel, eluent chloroform / hexane 2:3) to yield the products 9e-h.) and Amberlyst 15 (0.5 g, 20 % of aldehyde) in benzene (50 mL) was refluxed for 5 h.After the catalyst was filtered off, the solvent was evaporated in vacuo.The residue was dissolved in a mixture of benzene/hexane 1:4 and the hot solution was filtered through a pad of silica gel and kept to crystallise to yield 9h as a yellow powder (1.75 g, 92 %).