4, 5, 6, and 7-Hydroxybenzofuran: a unified strategy for a two-step synthesis of versatile benzofuranic building blocks

Over several decades, many different strategies have been reported to prepare 4, 5, 6, and 7-hydroxybenzofuran (HBF), which are very important synthetic intermediates. Interested in addition of their 2-lithiated O -protected derivatives to transient 1-pyrroline as a straightforward way to nicotinoids, we have developed a unique two-step procedure to obtain 4, 5, 6, and 7-HBF from 2,6, 2,5, 2-4-and 2,3-dihydroxyacetophenone, respectively, by conversion into 4, 5, 6-and 7-hydroxybenzofuranone and successive reduction of these latter with lithium borohydride. On the basis of the overall yields, the number of steps and the availability of the starting materials, such a synthetic strategy can be advantageously compared with the literature methods, here briefly reviewed, developed to synthesize the four HBFs.

Fulfilled SAR investigation of these hits requires, among others, characterization of a number of their regioisomers.In the case of the pyrrolidinyl benzofuran 5, this would mean availability of its 4-, 6-and 7hydroxy isomers.The recently published addition of 2-benzofuranyllithium to the cyclic imine generated in situ from N-lithiated pyrrolidine 12 suggests a straightforward way to these positional isomers and to series of regioisomers with other substituents in alternative to Negishi coupling, which would instead require pyrrolidine N-Boc protection, on one side, and bromine substituent at benzofuran C(2) on the other 13 (Figure 2).
Feasibility and advantages of such an approach are obviously conditioned by the ready accessibility of the four hydroxybenzofurans (HBFs), namely 4-hydroxy-, 5-hydroxy-, 6-hydroxy-, and 7-hydroxy benzofuran (4-, 5-, 6-, and 7-HBF respectively) and, consequently, of their properly O-protected derivatives, compared to that of the corresponding 2-bromo analogues (Figure 3).To our knowledge, the literature reports only the preparation of 2-bromo-6-HBF from 2,4-dihydroxybenzaldehyde, CBr4 and PPh3, 14 and, in our experience, the procedure can be reproduced for 2-bromo-5-HBF from 2,5-dihydroxybenzaldehyde, 6 but it is very problematic for 2-bromo-7-HBF from 2,3-dihydroxybenzaldehyde due to low yield.On the other hand, high-cost 2,6dihydroxybenzaldehyde discourages any attempt to convert it into 2-bromo-4-HBF.Many methods have been developed to synthesize the four positional isomers of benzofuran hydroxylated at the benzene ring.Almost all of them use a properly mono-or disubstituted phenol as a starting material and their key step is the cyclization to give the benzo-condensed five-membered heterocycle.The reverse strategy, namely the formation of the furo-condensed six-membered cycle, is rare.An example is the Diels-Alder reaction of 2-nitrofurane with Danishefsky's diene to give 5-HBF. 15he literature syntheses based on the formation of the five-membered heterocycle are classified in Table 1 according to the two starting synthons, that are a six-membered cyclic compound and a functionalized 1-3 carbons unit.6][27][28] Almost all the syntheses require at least three steps.The overall yields are all lower than 55%, except that of 6-HBF from 4-methoxysalicylaldehyde (73%), which is claimed in a paper dedicated to the improvement of 6-HBF synthesis. 27The simpler two-step procedures, reported for 4-HBF and 7-HBF, are not significantly ameliorative in spite of one less step. 25,28The least accessible HBF seems to be 7-HBF and the most critical reactions are generally aromatization and decarboxylation.Table 1.Synthetic strategies reported in the literature for the synthesis of HBFs: synthons, number of steps and yields *Overall yield reported for the last two steps of the synthesis of 3-methyl-5-HBF starting from propionaldehyde.**The synthesis was also accomplished starting from 4-benzyloxyphenol, obtained from hydroquinone, by four steps and 35% yield (ref. 21).

Results and Discussion
In search of a more efficient method applicable to the synthesis of all four HBFs, our attention was drawn to a one-pot conversion of 2,6-dihydroxyacetophenone (6) into 4-hydroxybenzofuran-3-one (10), claimed as highly efficient (>90% yield), by persilylation in THF, followed by treatment with N-bromosuccinimide and then with NaOH (Scheme 1). 29,30Such a transformation, abandoned by the authors because of the unsuccessful successive reduction to desired 4-hydroxydihydrobenzofuran ( 14) (Scheme 1), could be also applied to the three regioisomers of 2,6-dihydroxyacetophenone bearing only one of the two hydroxyls ortho positioned, namely 7, 8, and 9, so obtaining all the four positional isomers of hydroxybenzofuran-3-one (10-13) and, after carbonyl reduction and dehydration, the desired four HBFs.The planned strategy is shown in Scheme 1.
Scheme 1. Planned syntheses of the four regioisomeric hydroxybenzofurans from four positional isomers of dihydroxyacetophenone.
Uncertainties were connected to the one-pot obtainment of the intermediate 5-, 6-and 7hydroxybenzofuranones (11-13) from the starting dihydroxyacetophenones 7-9 according to the new procedure, but above all to the efficiency of the subsequent reduction of the hydroxybenzofuranones to the corresponding HBFs.
With regard to the first step, the experimental details of the one-pot conversion of 6 into 10 are reported only in patents [31][32][33][34] and with yields much lower ( 50%) than those mentioned above (>90%).Under less severe conditions of temperature (0 °C instead of -78 °C) and in shorter time than those reported in patents, we transformed 6 into 10 with 97% yield after chromatographic purification, thus confirming the high efficiency of the literature undetailed experimental procedures. 29,30,35Analogous results (86% yield) were obtained applying the same procedure to convert 8 into 12.It is to be noted that the conversion of unprotected 8 into the corresponding α-bromoacetophenone and the subsequent cyclization to 12 have been reported in 21% overall yield. 36Otherwise, the one-pot conversion of the dihydroxyacetophenones bearing the hydroxyls reciprocally para and ortho positioned, namely 7 and 9, to 11 and 13, respectively, was not so efficient likely because accompanied by oxidation reactions.The dihydroxyacetophenone 7 was persilylated, brominated and desilylated and the crude α-bromoacetophenone was cyclized by treatment with sodium methoxide in methanol under nitrogen to give 11, which was isolated as a crude by aqueous HCl/ethyl acetate extraction but not purified by chromatography.The dihydroxyacetophenone 9 was converted into the corresponding α-bromoacetophenone and, without isolation, cyclized to 13 by adding NaOH to the reaction mixture and then extracted, after acidification with HCl, into ethyl acetate and used as a crude in the successive reductive dehydration.
In the literature, this second step has been investigated only for 10 and 12.The authors, who reported the conversion of 6 into 10, observed that 10 is converted to a mixture of 4-HBF and of the undehydrated intermediate 2,3-dihydrobenzo[b]furan-3,4-diol by NaBH4. 29Difficulties in univocal reductive dehydration to 6-HBF without overreduction to 2,3-dihydrobenzo[b]furan-6-ol were reported for 12 by other researchers. 18hese screened a variety of reagents in THF, such as LiAlH4, DIBAL, BH3•THF, Red-Al, NaBH4 and LiBH4, concluding that LiBH4 followed by HCl/H2O quench was the best option giving minimum overreduction byproduct and the highest yield of 6-HBF (68%).We decided to use these conditions to reduce the four hydroxybenzofuranones.Pure 10 and 12 were converted into 4-HBF and 6-HBF with 76% and 60% yield respectively.Therefore, the overall yields from dihydroxyacetophenones 6 and 8 to the corresponding HBFs were 74% and 52% respectively.Crude 11 and 13 were reduced to 5-HBF and 7-HBF with final yields, calculated on the starting acetophenones 7 and 9, of 61% and 45% respectively.

Conclusions
In summary, a two-step procedure has been developed to obtain the four regioisomeric benzofurans hydroxylated at benzene ring from the four regioisomeric dihydroxyacetophenones bearing one of the two hydroxyls ortho positioned.The unitary approach is based on the conversion of dihydroxyacetophenones into hydroxybenzofuranones followed by the reduction to hydroxybenzofurans.Such a strategy was allowed by the successful application to all four substrates of the procedure reported for the one-pot conversion of 2,6dihydroxyacetophenone to 4-hydroxybenzofuran-3-one and then, as the second step, of the reported reduction of 6-hydroxybenzofuran-3-one to 6-HBF with LiBH4.Given the availability of the four starting ketones, the only two steps and the overall yields, the four procedures can be advantageously compared with the literature methods, here briefly reviewed, developed to prepare these important synthetic intermediates.

Experimental Section
General.All chemicals and solvents were used as received from commercial sources or prepared as described in the literature.Flash chromatography purifications were performed using Biotage® Isolera® flash purification system using KP-Sil 32-63 μm 60 Å cartridges and Merck Silica Gel 60 (0.040-0.063 μm).TLC analyses were performed using 0.25mm silica gel plates on aluminium foil, containing a fluorescent indicator (Macherey-Nagel Alugram® SilG/UV 254).The spots were visualized under UV light (λ 254nm).The staining of TLC plates was performed with potassium permanganate; Rf values are given for guidance. 1H and 13 C NMR spectra were recorded at 300 and 75 MHz using Varian Mercury 300 spectrometer.Chemical shifts are reported in ppm relative to residual solvent (CHCl3 and MeOH) as internal standard.HRMS spectra were acquired by using the orbitrap analyzer of a LTQ Orbitrap XL instrument.Sample was introduced by flow injection directly into the APCI interface (Finnigan IonMax).Sample flow (10 µL min -1 ) was mixed with 300 µL min -1 of water containing 0.1% HCOOH and nebulized by using 50 units of nitrogen (20 units of sheath gas, 30 units of auxiliary gas) at 400 °C.Ionization was achieved by 5 µA of corona discharge.Resolution was set at 100000 (FWHM at 400 m/z) and scan range was 100-500 m/z.Melting points were determined by Büchi Melting Point B-540 apparatus.
General procedure for the synthesis of compounds 10, 11, 12, and 13.LiHMDS (21.7 mL of 1 M solution in THF) was added dropwise to a stirred solution of proper dihydroxyacetophenone (1000 mg, 6.57 mmol) in anhydrous THF (10 mL) at 0 °C under N2.TMSCl (2.8 mL, 21.7 mmol) was then added dropwise.The resulting solution was stirred at 0 °C for 15 min.NBS (1.29 g, 7.23 mmol) was added and the resulting mixture was stirred at rt for 3 hours.For preparation of 10, 12 and 13, 1 M NaOH (20 mL) was added and the reaction mixture was stirred at rt for 15 min. 1 M HCl (30 mL) was added and the mixture was extracted with EtOAc (3 x 15 mL).The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give the crude product, which was purified by chromatography on silica gel (10 and 12) or directly used in the successive reduction step (13).In the case of 11, isolated as a crude and, analogously to 13, directly submitted to the successive reduction, a different procedure was followed after the 3 hours reaction with NBS.(13).Obtained from 2,3-dihydroxyacetophenone as a crude product and used in the successive reaction without purification; Rf (cyclohexane/EtOAc 7:3) 0.21.5-hydroxybenzofuran-3(2H)-one (11).LiHMDS (21.7 mL of 1 M solution in THF) was added dropwise to a stirred solution of 2,5-dihydroxyacetophenone (1000 mg, 6.57 mmol) in anhydrous THF (10 mL) at 0 °C under N2.TMSCl (2.8 mL, 21.7 mmol) was then added dropwise.The resulting solution was stirred at 0 °C for 15 min.NBS (1.29 g, 7.23 mmol) was added and the resulting mixture was stirred at rt for 3 hours.1 M HCl 1 M (30 mL) was added, and the mixture was extracted with EtOAc (3 x 15 mL).The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure.The crude was dissolved in MeOH (15 mL) and MeONa (391 mg, 7.23 mmol) was added under N2.The reaction mixture was stirred at rt for 1 hour.Then, 1 M HCl 1 M (30 mL) was added, and the mixture was extracted with EtOAc (3 x 15 mL).The combined organic