Synthesis of 3-benzoyl-4-benzylfurans structural related to furolignans

Abstract Furolignan-type natural products, possessing important biological properties, have been synthesized from a commercially available furan. The elaborated synthetic strategy is based on an innovative Friedel-Crafts reaction starting from an alcohol or a carboxylic acid and triflic anhydride as promoter. Through this synthetic strategy, furolignans having two different aryl groups have been obtained. The products have been evaluated for their antimicrobial properties on Gram positive and Gram negative bacteria, in order to compare their biological activities with those of natural analogues. Graphical Abstract


Introduction
Lignans are one of the biggest groups of natural products and have many biological effects, including anti-microbiological activity (Saleem et al. 2005;Teponno et al. 2016). The significant bioactivities and structural diversity of lignans have triggered a great amount of synthetic work (Akiyama et al. 2007; Pohjoisp€ a€ a and W€ ah€ al€ a 2013). Classical lignans are phenylpropane dimers linked in a b-b' (8-8') fashion and comprise six subtypes (Pan et al. 2009). Lignan subtypes such as dibenzylbutane, dibenzylbutyrolactol and dibenzylbutyrolactone are present in many plant species (Barros et al. 2009;Chang et al. 2013;Fang et al. 2014;Yang et al. 2015;Hodaj et al. 2017;Kee and Hong 2017) and some examples are reported in Figure 1. These lignans have a 3,4dibenzylfuran carbon skeleton. On this basis we developed a method for the preparation of furolignan-like compounds starting from a commercially available furan. The elaborated synthetic strategy is based on the use of triflic anhydride (Tf 2 O) as promoter in Friedel-Crafts reactions starting from an alcohol or a carboxylic acid instead of the classical approach with a chloride (Khodaei et al. 2007;Khodaei and Nazari 2012). Various electrophilic activations using this innovative Friedel-Crafts (FC) reactions have found broad application in the synthesis of interesting aromatic compounds.
The products have been analysed for their antimicrobial properties on Gram positive and Gram negative bacteria.

Results and discussion
The reactant alcohol (1) was prepared by reduction of dimethyl 3,4-furandicarboxylate with NaBH 4 under specific conditions (Iesce et al. 2016). Methyl 4-(hydroxymethyl) furan-3-carboxylate (1) was subjected to a Friedel-Crafts alkylation according to the Khodaei-Nazari procedure (Khodaei and Nazari 2012). This procedure includes the addition of an arene and a monoalcohol to a mixture of Ph 3 PO and Tf 2 O (Scheme 1). reacts exothermically with Ph 3 PO in CH 2 Cl 2 to give a white precipitate of the corresponding triphenylphosphine ditriflate (TPPD), a salt, commonly called Hendrickson's reagent, that shows to be a powerful dehydrating agent and a promoter for the FC benzylation of arenes with benzyl alcohols (Khodaei and Nazari 2012). This alkylation was performed using a series of aromatic substrates such as anisole (2a), 1,2-dimethoxybenzene (2b), benzodioxole (2c) and phenol (2d). In general, to a solution of Ph 3 PO in dry dichlorometane, Tf 2 O was added at 0 C and the mixture was stirred for 15 min at room temperature. Then, arene 2 and furanyl alcohol (1) in equimolar amount were added and the mixture was stirred for 2 h. Upon completion of the reaction, monitored by TLC, the organic solvent was evaporated and the products were isolated by silica gel column chromatography. The alkylation results, reported in Scheme 1, evidence that the reaction occurs with yields of about 40% except for 1,3benzodioxole (2c, 27%) and phenol (2d, <5%). A mixture of the two isomers with the methoxyl group in the para or ortho position (3a and 4a) were obtained in the reaction with anisole (Scheme 1, entry 1), in 5:3 ratio, respectively. A similar result was observed for benzodioxole (2c) that led to isomers 3c and 4c in c.a. 3:1 ratio (Scheme 1, entry 3). In order to improve the yield with phenol, it was protected using tertbutyldimethylsilyl chloride (TBSCl), as reported in literature (Brigante et al. 2006). The alkylation was conducted with a slight excess of silylated phenol 2d' (1: 1.3 equiv.; Scheme 1, entry 5) and the non-protected product 3d, with a yield of 40% was obtained. The alkylated furans (3a,b and 4a) and the mixture 3c/4c were hydrolysed with KOH in methanol to obtain the carboxylic acids (5 and 6) in high yields. The furanyl acids obtained were subjected to Tf 2 O-catalyzed Friedel-Crafts acylation (Khodaei et al. 2007;Comegna et al. 2012) in order to obtain the target products with a lignan-like structure (Scheme 2).
As for the FC alkylation reaction, it is reported in literature that the FC acylation of aromatic compounds with carboxylic acids as acylating agents in the presence of Tf 2 O occurs without using any catalyst and with high efficiency and high selectivity (Khodaei et al. 2007). Previously in our laboratory (Comegna et al. 2012), 3-or 4-aroylfurans were prepared from a readily accessible precursor, 3-methoxycarbonyl-2- phenylfuran-4-carboxylic acid, by simple tuning the reaction conditions in Friedel-Crafts acylation promoted by triflic anhydride.
The same experimental conditions (reagents ratio, temperature, neat or solvent) were applied to examine the chemical behaviour of furanyl acids (5 and 6) in the Tf 2 O-catalyzed Friedel-Crafts acylation.
Initially, investigation was followed on the reaction of acid 5c/6c using anisole as the aryl reagent (Scheme 2). The reaction was carried out by dissolving acid 5c in large excess of anisole (65 equiv.) and adding Tf 2 O (2.5 equiv.) at low temperature (-20 C). The resulting mixture was stirred at room temperature for 4 h, monitored by TLC, but no reaction occurred.
In an attempt to get results using this reaction, several tests were performed. First, it was tried to lower the acid: arene ratio at 1:5, keeping the acid: Tf 2 O ratio unchanged, continuing the addition of triflic anhydride at -20 C and extending the reaction times (overnight at room temperature).
Under these conditions the FC acylation of furancarboxylic acid 5c/6c with anisole (2a) occurred with a 20% of yield. However, no results were observed with different acylating agents on the same furancarboxylic acid 5c/6c nor using anisole with the acids 5a/6a or 5b.
Then we planned to work at higher temperatures while maintaining the same ratio between the reagents.
In general, acid 5c/6c was dissolved in dry solvent and then arene (5 equiv.) was added. The mixture was cooled at 0 C and Tf 2 O was added dropwise at this temperature. After 15 min at 0 C the resulting mixture was heated up to the solvent reflux temperature and stirred at this temperature for about 10 h.
The reaction was tested with two solvents with different boiling points, 1,2dichloroethane and dichloromethane, in the same conditions.
Using 1,2-dichloroethane as solvent, the reaction was tested with acids 5a, 5 b and 5c/6c using 1,3-benzodioxole, phenol and anisole as arene, respectively, but all attempts were unsuccessful. When, instead, dichloromethane was used as solvent, and prolonging the reaction times, products 7a-c and 8a, 8c with lignan-like structure were obtained (Scheme 2). Only an intractable mixture was obtained with protected phenol (2d') and no acylated product was observed.
In order to obtain information on their antimicrobial properties on Gram positive and Gram negative bacteria compared to that of their natural analogues, we decided to test both the furolignan-like products obtained and reaction intermediates (3d and 5c). The compounds were serially diluted (from 128 to 0.125 lg/mL) and tested on two Gram-positive clinical isolates (Staphylococcus aureus and S. epidermidis) and one Gram-negative (Pseudomonas aeruginosa). Minimal inhibitory concentrations (MIC) of compounds was determined in specific culture medium by the broth microdilution assay, according to the European Committee on Antimicrobial Susceptibility Testing.
The results obtained showed that none of the compounds tested were effective in reducing bacteria growth (Data not shown).

Reduction of dimethyl 3,4-furandicarboxylate
Methanol (0.8mL) was added over a period of 1 h to the refluxing mixture of NaBH 4 (1.2 mmol) and diester (1 mmol) in t-BuOH (4 mL). After the addition of MeOH, the reaction mixture was refluxed for 1 h. After the complete conversion of the reagents, monitored with TLC, the reaction was quenched by the addition of HCl (0.5 M). The organic solvent was evaporated on a rotary evaporator, and the residue was extracted with dichloromethane (4 Â 10 mL). The organic layer was collected, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue that was purified by column chromatography (petroleum ether/ethyl acetate gradient).

General procedure for Tf 2 O/Ph 3 PO mediated Friedel-Crafts alkylation of furanyl alcohol
To a solution of Ph 3 PO (0.6 mmol) in dry dichlorometane (1 mL), Tf 2 O (0.1 mL, 0.6 mmol) was added at 0 C and the mixture was stirred for 15 min at room temperature. Then, arene (0.5 mmol) and furanyl alcohol (0.5 mmol in 1 mL of dry dichloromethane) were added. The mixture was stirred for 2 h. Upon completion of the reaction, monitored by TLC, the organic solvent was evaporated and the residue was chromatographed by preparative TLC using a mixture of petroleum ether/ethyl acetate (4:1) as eluent.

General procedure for synthesis of furanyl acids
The monoester (0.5 mmol) was dissolved in MeOH (2.5 mL) and KOH 2.5 M (2.5 mmol) was then added. The resultant mixture was refluxed for 2 h. After the complete conversion of the reagents, the MeOH was evaporated on a rotary evaporator, and the residue was extracted with diethyl ether (2 Â 5 mL). The aqueous layer was acidified slowly with HCl 2 M up to neutral and then was extracted with ethyl acetate (3 Â 5 mL). The organic layer was collected, dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the acid that does not require further purification.

General procedure for Tf2 2 O-mediated Friedel-Crafts acylation of acids 5
Crude acid 5 (0.5 mmol) was dissolved in CH 2 Cl 2 dry (6 mL) and then arene (2.5 mmol) was added. The mixture was cooled to 0 C and Tf 2 O was added dropwise at this temperature. The resulting mixture was stirred under N 2 atmosphere at 0 C for 10 minutes, then was brought at room temperature and finally was heated up to 40 C in reflux for 23 h. On completion of the reaction, controlled by TLC, the mixture was washed with saturated aq. NaHCO 3 solution and extracted with CH 2 Cl 2 (3 Â 5 mL). The organic layer was washed with H 2 O, collected, dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give a residue that was chromatographed on silica gel with a gradient of petroleum ether and ethyl acetate.

Conclusion
In conclusion, a concise and divergent synthesis of furolignan-type natural products has been accomplished from commercial furan by a selective reduction and, as the key step, an innovative Friedel-Crafts reaction which could be used for the preparation of natural products for biological and medical studies.

Supplementary material
General experimental procedures, spectral data of synthetized compounds, microbroth dilution assay and 1 H and 13 C NMR experiments of the compounds (Figures S1-S26) are available online.

Disclosure statement
No potential conflict of interest was reported by the authors.