A Recyclable Palladium-Catalyzed Synthesis of 2-Methylene-2,3-Dihydrobenzofuran-3-ols by Cycloisomerization of 2-(1-Hydroxyprop-2-ynyl)phenols in Ionic Liquids

A recyclable palladium-catalyzed synthesis of 2-methylene-2,3-dihydrobenzofuran-3-ols 2 by heterocyclization of 2-(1-hydroxyprop-2-ynyl)phenols 1 in an ionic liquid medium (BmimBF4) is presented. The process takes place under relatively mild conditions (100 °C, 5 h) in the presence of catalytic amounts (2 mol %) of PdI2 in conjunction with KI (5 equiv with respect to PdI2) and an organic base, such as morpholine (1 equiv with respect to 1), to give 2 in high yields (70%–86%). The PdI2-KI catalytic system could be recycled up to six times without appreciable loss of activity. Moreover, products 2 could be easily converted in a one-pot fashion into 2-hydroxymethylbenzofurans 3 (52%–71%, based on 1) and 2-methoxymethylbenzofurans 4 (52%–80%, based on 1) by acid-catalyzed allylic isomerization or allylic nucleophilic substitution.


Introduction
Metal-catalyzed heterocyclization reactions are a powerful methodology for the direct synthesis of substituted heterocyclic derivatives starting from readily available substrates [1][2][3][4][5][6][7][8][9][10][11]. The process OPEN ACCESS occurs through the activation of an unsaturated bond by coordination to the metal center, followed by endo or exo intramolecular attack by the nucleophilic group (YH) and protonolysis or vice versa (Scheme 1-the case of a functionalized alkyne is shown). In particular, we have reported several metal-catalyzed heterocyclizations of acetylenes, bearing a nucleophilic group in a suitable position for cyclization, which have proved valuable for the preparation of a variety of important heterocycles, including furans, pyrroles, thiophenes, and benzothiophenes [12][13][14][15][16][17][18][19][20]. Scheme 1. Metal-catalyzed heterocyclization of acetylenes bearing a suitably placed nucleophilic group leading to heterocycles through activation of the triple bond by the metal species followed by intramolecular nucleophilic attack and protonolysis. Recently, we have reported a novel approach to the synthesis of 2-methylene-2,3dihydrobenzofuran-3-ols 2 by Pd-catalyzed heterocyclization of 2-(1-hydroxyprop-2-ynyl)phenols 1, carried out in MeOH in the presence of PdX 2 as catalyst in conjunction with KX (X = Cl, I) and morpholine as the base, necessary for substrate deprotonation [18]. Either 5-exo-dig intramolecular attack to coordinated triple bond (path a) or triple bond insertion into the Pd-O bond of a phenoxypalladium intermediate (path b) may take place, according to Scheme 2 [18].

Results and Discussion
2-(1-Hydroxy-1-phenylprop-2-ynyl)phenol (1a) was chosen as the model substrate for testing the reactivity of 2-(1-hydroxyprop-2-ynyl)phenols in ionic liquids. The reaction of 1a, carried out in BmimBF 4 as the solvent at 70 °C for 5 h, in the presence of 2 mol % of PdI 2 in conjunction with KI (5 equiv with respect to PdI 2 ) and morpholine (1 equiv. with respect to 1a), led to the formation of 2-methylene-3-phenyl-2,3-dihydrobenzofuran-3-ol (2a) in 60% isolated yield at 80% substrate conversion ( Table 1, entry 1). This initial result clearly confirmed the feasibility of the process in an ionic liquid as the reaction medium. Substrate conversion reached 100% either after 8 h at the same temperature (with a 2a yield of 82%, Table 1, entry 2) or after 5 h at 100 °C (with a 2a yield of 86%, Table 1, entry 3). The reaction also worked well with 1 mol % of catalyst, as shown in Table 1, entry 4 (2a yield was 80%). On the other hand, the use of 4 mol % of KI or the use of PdCl 2 /KCl instead of PdI 2 /KI led to inferior results (Table 1, entries 5 and 6, respectively). Lower yields of 2a were also obtained working in other ILs, such as BmimCl, BmimPF 6 , BmimN(CN) 2 , or BmimOTf (Table 1, entries 7-10).
The next experiments were aimed at verifying the recyclability of the catalyst-IL system and at generalizing the process to other variously substituted substrates, using BmimBF 4 as the reaction medium at 100 °C for 5 h. Regarding the recycling experiments, the reaction crude deriving from the reaction carried out under the same conditions as those reported in Table 1, entry 3, was extracted several times with diethyl ether, to isolate the product, while the residue (containing the catalyst dissolved in the IL), after drying under vacuum, was used again by adding to it fresh substrate 1a and morpholine (1:1 ratio). After stirring at 100 °C for 5 h, 2a was obtained again, with practically the same yield as the parent reaction (85%, Table 2, entry 1, run 2). The recycling procedure was then repeated up to 5 times, without any appreciable loss of catalytic activity (Table 2, entry 1, runs 3-7).   The method was then extended to other 2-(1-hydroxyprop-2-ynyl)phenols 1b-g, bearing different (either electron-withdrawing or electron-donating) substituents on the aromatic ring and at the benzylic position. As can be seen from the results shown in Table 2, entries 2-7, good yields of the corresponding methylenedihydrobenzofurans 2b-g were consistently obtained. We also checked the catalyst-solvent recyclability in all cases, still with satisfactory results, products being obtained in comparable yields with respect to the parent reactions ( Table 2, entries 2-7).
2-Methylene-2,3-dihydrobenzofuran-3-ols 2 are known to be useful precursors for the preparation of functionalized benzofurans [18,42]. In particular, we previously reported that they can easily undergo acid-catalyzed allylic isomerization to give 2-hydroxymethylbenzofurans 3 or acid-catalyzed allylic nucleophilic substitution to give 2-methoxymethylbenzofurans 4 [18]. We have now found that it is possible to directly obtain either benzofurans 3 or 4 in a one-pot fashion by Pd-catalyzed cycloisomerization of 1 in BmimBF 4 , followed by acid catalyzed allylic isomerization or nucleophilic substitution, without the need for isolating compounds 2. Thus, the reaction mixture resulting from the cycloisomerization process was allowed to cool down to room temperature, and then H 2 SO 4 in water or in MeOH was added. After 3-18 h at 100 °C, the corresponding benzofuran derivatives 3 and 4 were obtained in high yields (Table 3). Clearly, no IL recyclability was possible for this one-pot transformation.

General
Melting points were taken on a Reichert Thermovar apparatus and are uncorrected. 1 H-NMR and 13 C-NMR spectra were recorded at 25 °C in CDCl 3 solutions with a Bruker DPX Avance 300 spectrometer operating at 300 MHz and 75 MHz, respectively, with Me 4 Si as internal standard. Chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively. IR spectra were taken with a JASCO FT-IR 4200 spectrometer. Mass spectra were obtained using a Shimadzu QP-2010 GC-MS apparatus at 70 eV ionization voltage. Microanalyses were carried out with a Carlo Erba Elemental Analyzer Mod. 1106. All reactions were analyzed by TLC on silica gel 60 F 254 (Merck) or on neutral alumina (Merck) and by GLC using a Shimadzu GC-2010 gas chromatograph and capillary columns with polymethylsilicone + 5% polyphenylsilicone as the stationary phase (HP-5). Column chromatography was performed on silica gel 60 (Merck, 70-230 mesh) or neutral alumina 90 (Merck, 70-230 mesh). Evaporation refers to the removal of solvent under reduced pressure.

Preparation of Ionic Liquids
Ionic liquid BmimOTf [44] was prepared according to a literature procedure. All other ionic liquids were prepared as previously described [17].

General Procedure for the PdI 2 /KI-Catalyzed Cycloisomerization of 2-(1-Hydroxyprop-2ynyl)phenols 1 to Give 2-Methylene-2,3-Dihydrobenzofuran-3-ols 2
To a Schlenk flask containing PdI 2 (1.8 mg, 5.0 × 10 −3 mmol), KI (4.2 mg, 2.5 × 10 −2 mmol) and BmimBF 4 (1 mL) was added, under nitrogen, a solution of 1 (0.25 mmol) in Et 2 O (1.5 mL). The diethyl ether was eliminated under vacuum, and then morpholine (22.0 mg, 0.25 mmol) was added under nitrogen. The resulting mixture was allowed to stir under nitrogen at 100 °C for 5 h. After cooling, the mixture was extracted with Et 2 O (6 × 2 mL), to separate the product, while the residue, still containing the catalysts dissolved in the IL, was used as such for the recycling experiments (see below). The collected ethereal phases were concentrated, and products 2 were purified by column chromatography on silica gel using hexane-AcOEt from 95:5 to 9:1 as the eluent. The yields obtained in each experiments are reported in Table 2.
Recycling Procedure. To the residue obtained as described above, still containing the catalyst dissolved in the ionic liquid, was added under nitrogen a solution of 1 (0.25 mmol) in Et 2 O (1.5 mL). Diethyl ether was removed under vacuum, morpholine (22.0 mg, 0.25 mmol) was added, and then the same procedure described above was followed.

General Procedure for the One-Pot Synthesis of 2-Hydroxymethylbenzofurans 3 and 2-Methoxymethylbenzofurans 4 Starting From 2-(1-Hydroxyprop-2-ynyl)phenols 1
To a Schlenk flask containing PdI 2 (1.8 mg, 5.0 × 10 −3 mmol), KI (4.2 mg, 2.5 × 10 −2 mmol) and BmimBF 4 (1 mL) was added, under nitrogen, a solution of 1 (0.25 mmol) in Et 2 O (1.5 mL). The diethyl ether was eliminated under vacuum, and then morpholine (22.0 mg, 0.25 mmol) was added under nitrogen. The resulting mixture was allowed to stir under nitrogen at 100 °C for 5 h. After cooling, a solution of H 2 SO 4 in ROH (R = H or Me, 0.75 M) (670 μL, 0.5 mmol) was added under nitrogen (together with 100 μL of MeOH when R = Me), and the mixture was allowed to stir at 100 °C for 3 h (R = H) or overnight (18 h, R = Me). After cooling, the mixture was extracted with Et 2 O (6 × 2 mL). The collected ethereal phases were concentrated, and products 3 (R = H) and 4 (R = Me) were purified by column chromatography on silica gel using hexane-AcOEt from 95:5 to 9:1 as the eluent. The yields obtained in each experiment are reported in Table 3.

Characterization of Products
All products 2, 3, and 4 were characterized by comparison with the characterization data already reported by us [18].