Syntheses of 3-hydroxymethyl-2,3-dihydrobenzofurans and 3-hydroxymethylbenzofurans

Reactions of 2-hydroxyphenylmethanones 8 with 1-chloro-1-(benzotriazol-1-yl)alkanes 9 give intermediates 10a–h , which were converted by trimethylsulfonium iodide to oxirans 11a–h . Treatment of 11a–h with LDA gave either 3-hydroxymethyl-2,3-dihydrobenzofurans or 3-hydroxymethylbenzofurans depending on substituents.

Compounds 11a-h were treated with an equivalent amount of LDA in THF at a temperature ranging from -78 °C to 20 °C.The anion formed by lithiation of the benzotriazole α-carbon in 1-(2-oxiranylphenoxymethyl)-benzotriazoles 11a-h selectively opens the oxiran ring to form 2,3dihydrobenzofurans 12a-h.To support the reaction pathway proposed in Scheme 2 for benzofurans 13a-f, and to investigate the accessibility of the benzotriazolyl group for substitution in 12a-f, we isolated and characterized compounds 12d-syn, 12d-anti, 12f-syn, and 12f-anti and used them for the preparation of benzofurans 13d,f.We also prepared compound 12g, which was formed exclusively as the anti diastereoisomer.In the case of 12h, we obtained both syn and anti diastereoisomers.The 1 H NMR spectra of 12d,f-g show no characteristic signals assigned to the oxiranyl rings of compounds 11d,f-h in the range 2.2-4.1 ppm.The 13 C NMR spectra of 12d,f-g no longer show the carbon signal in 74-84 ppm range, which corresponds to the carbon between the benzotriazole and phenolic oxygen in 11d,f-h.For 12d,fh new signals in the range 93-104 ppm were assigned to the C2 carbons of the 2,3dihydrobenzofuran rings.
The structures of diastereoisomers 12f-anti, 12g-anti, 12h-syn and 12h-anti were unambiguously determined by single crystal X-ray structure determination.Figure 1 shows a perspective view of the molecular structure of a representative example (12h-syn), which ascertains both, the structure and relative stereochemistry of this isomer.Interestingly, in each of the four crystal structures determined, the hydroxymethyl substituent participates in an intermolecular hydrogen bond to the N3 nitrogen atom of an adjacent molecule in the solid state.The signals for the methylene protons of the 3-hydroxymethyl group in 12f-syn in 1 H NMR appear as two multiplets at 3.93-4.01ppm, 4.04-4.11ppm.The signals for the same protons of 12f-anti appear as two multiplets at 3.37-3.48ppm, 3.72-3.82ppm.The signals for the corresponding protons for the one of the diastereoisomers of 12d in the 1 H NMR spectrum appear as two multiplets at 3.18-3.28ppm, 3.61-3.69ppm; the same protons for the second diastereoisomer overlapped in one multiplet at 4.02-4.18ppm.We assigned the signals at 3.18-3.28ppm, 3.61-3.69ppm to the syn-isomer and that at 4.02-4.18ppm to the anti-isomer.The ratios syn:anti for compounds 12d, 12f, and 12h were approximately 34:66, 32:68, and 59:41, respectively.The structures of compounds 12d, 12f, 12g and 12h were also supported by their 1 H NMR and 13 C NMR spectra.
Treatments of 2,3-dihydrobenzofurans 12d, 12f and oxirans 11a-f with two equivalents of LDA in THF at a temperature ranging from -78 °C to 20 °C afford the corresponding 3hydroxymethylbenzofurans 13a-f in yields of 66-85%.The structures of compounds 13a-f were deduced from their 1 H NMR and 13 C NMR spectra.Unlike 12d, 12f and 11a-f, the 1 H NMR spectra of 13a-f show no characteristic signals for a N-substituted benzotriazolyl group (in the range 7.3-8.1 ppm) or for an oxiranyl ring (in range 2.2-4.1 ppm).The 13 C NMR spectra of 13af also no longer show any signal in the range 74-84 ppm, which corresponds to the carbon between the benzotriazole and phenolic oxygen nor any benzotriazole signals at 126-128 ppm, 131-133 ppm and 146-147 ppm, as were assigned for 11a-f.We also tried to substitute the benzotriazole group in 2-(benzotriazol-1-yl)-2,3-dihydrobenzofurans 12f,g.Compound 12f, when treated with a Grignard reagent (3 eq., benzyl magnesium bromide or isopropyl magnesium bromide) in THF under reflux, unexpectedly gave only the corresponding benzofuran 13f (45%), as the result of benzotriazole elimination.Compound 12g was unreactive to these Grignard reagents.Attempts to use a zinc reagent (3 eq., isopropyl zinc bromide) in THF on 12f were also unsuccessful.In an attempt to substitute benzotriazole with hydrogen, compound 12g was reacted with lithium naphthalenide 16 (3 eq.) in THF at temperatures ranging from -40 to 20 °C followed by the addition of water.This gave only the product 14.Structure of 14 was deduced from its 1 H and 13 C NMR spectra, which showed a set of signals characteristic for a N-substituted benzotriazole group, two broad singlets at 5.3 ppm and 10.1 ppm corresponding to the two hydroxy groups and the four doublets corresponding to the two methylene groups, which do not have neighboring protons.

Conclusions
An efficient method for preparation of 3-hydroxymethyl-2,3-dihydrobenzofurans and 3hydroxymethylbenzofurans has been developed using benzotriazole mediated benzofuran ring closure.The application of this method allows the preparation of the 3-hydroxymethyl-2,3dihydrobenzofurans 12d,f-h and 3-hydroxymethylbenzofurans 13a-f in good yields, starting from readily available salicylic aldehydes.

Experimental Section
General Procedures.Melting points were determined on a hot-stage apparatus and are uncorrected.NMR spectra were recorded in CDCl 3 with TMS as the internal standard for 1 H (300 MHz) or a solvent as the internal standard for 13 C (75 MHz).Micro elemental analyses were performed on a Carlo Erba EA-1108 elemental analyzer.LDA was used freshly prepared from nbutyllithium and di-iso-propylamine.Di-iso-propylamine was dried over calcium hydride.DMF and DMSO were dried over molecular sieves.Column chromatography was conducted with silica gel 200−425 mesh.

General procedure for the preparation of O-alkylated (2-hydroxyphenyl)methanones (10a-h)
A mixture of (2-hydroxyphenyl)methanone 8 (20 mmol), 1-benzotriazol-1-ylalkyl chloride 9 (22 mmol) and potassium carbonate (3.6 g, 26 mmol) in DMF (50 mL) was stirred at 40−50 °C for 4 h.Then, the reaction mixture was cooled to 10-15 °C and ice-water (approx.30-40 mL) was slowly added.The precipitate was filtered off, washed with water and dried in vacuum.The products 10b, 10d were extracted with ethyl acetate, the extract was washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure.The residue was purified by column chromatography on silica gel.

General procedure for the preparation of oxirans (11). Method A for 11a-d and 11g-h
Potassium tert-butoxide (0.9 g, 8 mmol) was added to a stirred solution of the 2-(benzotriazol-1ylmethoxy)phenylmethanone 10 (2 mmol) and trimethylsulfonium iodide (1.63 g, 8 mmol) in DMSO (20 mL) at 10-15 °C.The reaction mixture was stirred at the same temperature for 1 h, then it was allowed to warm to 20-25 °C and kept at this temperature for 4 h.Then, ice-water was added and the product was extracted with dichloromethane or ethyl acetate.This extract was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure.The residue was purified by column chromatography on silica gel.
ISSN 1551-7012 Page 55 © ARKAT USA, Inc Method B for 11e-f.A vigorously stirred mixture of 10 (3 mmol) with trimethylsulfonium iodide (0.82 g, 4 mmol) in the presence of tetrabutylammonium iodide (50 mg, 0.13 mmol) in dichloromethane (10 mL) and 50% aqueous NaOH (10 mL) was refluxed under a nitrogen atmosphere for 12−48 h.When 10 was consumed (as monitored by TLC), the product was extracted with dichloromethane.The extract was dried over magnesium sulfate and the solvent was evaporated to give the crude product 11 in approximately 90% purity.These products were used for preparation of compound 12 and 13.The oxiran 11e can be additionally purified by column chromatography on silica gel with a mixture of ethyl acetate-hexanes (1:3).

General procedure for the preparation of compounds 13a-f
A solution of LDA (2.0 mmol) in THF was added to a stirred solution of 11 or 12 (0.9 mmol) in THF (10 mL) at -78 °C and the reaction mixture was stirred for 12 h.The reaction temperature was raised to 20-25 °C and the reaction mixture was kept at this temperature for an additional 12 h.Then, the reaction mixture was quenched with saturated aqueous NH 4 Cl and the product was extracted with ethyl acetate.The extract was washed with water, dried and evaporated.The product 13 was purified by gradient column chromatography using mixtures of ethyl acetate with hexanes.

Figure 1 .
Figure 1.Perspective view of the X-ray structure of 12h-syn.

Table 1 . Preparation of intermediates 10, 11, 12 and 3-hydroxymethylbenzofurans 13
a was not prepared.b two diastereomers.c yield for Method B (see experimental section).