Benzofuran structures and their derivatives are found in many compounds that are of current interest due to their broad range of biological activity. A wide variety of existing drugs,which contain benzofurans have been developed. Amiodarone ^[1] is an antiarrhythmic drug developed in the early 1960s. Galanthamine ^[2] is marketed under the name Reminyl for the treatment of Alzheimer’s disease. Ramelteon ^[3] is developed by the Takeda Corporation and approved in the US for the treatment of insomnia. Prucalopride ^[4] is a new drug developed by Janssen for the treatment of irritable bowl syndrome and constipation.

Based on the wide range activity of benzofuran and its derivatives,the synthesis of such compounds has been a focus in organic chemistry research. 3-Hydroxymethylbenzofuran,an important intermediate of active benzofuran derivatives ^{[5, 6, 7, 8]},is usually synthesized by the reduction of benzofuran-3-carbaldehyde with NaBH₄ ^{[9, 10]}. In this paper,we report a new method for the synthesis of 3-hydroxymethylbenzofuran.

All reagents were obtained commercially and used without further purification. The solvents used were all of AR grade and were dried over standard drying agents or freshly distilled where necessary. ¹H NMR and ¹³C NMR spectra were recorded in CDCl₃ on a Varan Mercury300 spectrometer using TMS as an internal standard. Coupling constant (J) values were given in Hz. Mass spectra were determined with Agilent 6520 Accurate-Mass Q-TOF LC/MS.

General procedure for 3-hydroxymethylbenzofuran derivatives: To a solution of 2 (1 mmol) in THF (2 mL),HCl (1 mol/L,2 mL) was added. The mixture was heated to 60 ℃ and stirred for 2-12 h and then cooled to room temperature. The reaction was quenched with saturated NaHCO₃ aqueous,extracted with EtOAc (3×5 mL) and washed with water. The organic layer was dried (Na₂SO₄),filtered, and evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (PE:EtOAc = 5:1) to afford 3 ^[11] (Table 1).

Table 1

Table 1 Synthesis of 3-hydroxymethylbenzofuran derivatives.

Table 1 Synthesis of 3-hydroxymethylbenzofuran derivatives.

During the study on selectively cleavage of the MOM group on alcoholic hydroxyl of compound 1,an interesting result was observed. Treatment of compound 1 with 1 mol/L HCl in MeOH led to compound 2 as the major product. However,the reaction was carried out in THF,compound 3 was detected as the major product (Scheme 1).

Scheme 1

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Scheme 1 Different deprotection products in different solvent.

The probable mechanism of this formation was shown in Scheme 2. In an acidic condition,the MOM groups on alcoholic hydroxyl and phenolic hydroxyl were both removed to produce intermediate 4,which was cyclized to produce α-hydroxyhemiacetal intermediate 5 by intramolecular addition. A similar mechanism for this formation had been reported by Nishino ^[12]. The intermediate 5 was dehydrated to produce intermediate 6,which was then converted to compound 3 by addition and electron transfer. This is a new pathway to construct 3-hydroxymethylbenzofuran derivatives.

Scheme 2

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Scheme 2 Probably mechanism for 3-hydroxymethylbenzofuran derivatives formation.

To investigate this proposed mechanism,the designed reaction was carried out. Deprotection of compound 7 afforded tautomeric intermediate 4 and 5 (1:1),as revealed by ¹H NMR spectroscopy ^[13]. The tautomeric mixture was treated with TBSCl in alkaline condition to obtain compound 8. The tautomeric mixture was treated in acidic condition to obtain compound 3 (Scheme 3). This supported that intermediate 4 is not stable in the solution,as the hypothesized mechanism predicts. The reaction equilibrium was moved to intermediate 5 to give 3 after addition and electron transfer.

Scheme 3

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Scheme 3 Certification of the probably mechanism.

To study the applicability of this new method,other substances were discussed as follows (Table 1): when the aromatic nucleus was benzene,the yield of this product was excellent,but when the aromatic nucleus was naphthalene,the product was barely detected by LC-MS. This yield could not be improved,not even by lowering the reaction temperature or reducing the concentration of hydrochloric acid. We proposed that the naphthalene-type intermediate was unstable,resulting in the decomposition of the substances.

In conclusion,we developed a new method to furnish 3- hydroxymethylbenzofuran derivatives. This reaction was carried out under acidic condition in THF at reflux. The key step of the reaction mechanism for this process was a chemical equilibrium shift of tautomer. Further studies and the extensions of this method in the preparation of other 3-hydroxymethylbenzofuran derivatives are currently underway.

The project was supported by the National Mega-Project for Innovative Drugs (No. 2012zx09301002-002) and State Key Laboratory of Bioactive Substance and Function of Natural Medicines.