Highly Efficient Synthesis of 2-Substituted Benzo[b]furan Derivatives from the Cross-Coupling Reactions of 2-Halobenzo[b]furans with Organoalane Reagents

Abstract A highly efficient and simple route for the synthesis of 2-substituted benzo[b]furans has been developed by palladium-catalyzed cross-coupling reaction of 2-halobenzo[b]furans with aryl, alkynyl, and alkylaluminum reagents. Various 2-aryl-, 2-alkynyl-, and 2-alkyl-substituted benzo[b]furan derivatives can be obtained in 23–97% isolated yields using 2–3 mol% PdCl2/4–6 mol% XantPhos as the catalyst under mild reaction conditions. The aryls bearing electron-donating or electron-withdrawing groups in 2-halobenzo[b]furans gave products in 40–97% isolated yields. In addition, aluminum reagents containing thienyl, furanyl, trimethylsilanyl, and benzyl groups worked efficiently with 2-halobenzo[b]furans as well, and three bioactive molecules with 2-substituted benzo[b]furan skeleton were synthesized. Furthermore, the broad substrates scope and the typical maintenance of vigorous efficiency on gram scale make this protocol a potentially practical method to synthesize 2-substituted benzo[b]furan derivatives. On the basis of the experimental results, a possible catalytic cycle has been proposed.

2-Substituted benzo [b]furans are important structural scaffolds found in many natural products and pharmaceutical products. 1,2 Some of these compounds have been known to exhibit anti-inflammatory, 3 antitumor, 4 anticancer, 4,5 lipoxygenase inhibitor, 6 antifungal, 7 antiplasmodial, 8 antioxidant, 9 anti-HIV, and estrogenic activity 10 properties. In addition, they serve as building blocks for many organic transformations. 11 Thus, their synthesis and applications have attracted considerable attention in the chemical and pharmaceutical industries over the past decades. 2b,c Developing some simple and effective method for the synthesis of 2-substituted benzo [b]furans from simple and easily available organic compounds is very important. In addition to the traditional synthetic methods, 12 transition-metal-mediated cross-coupling method provides an effective route for the synthesis of functionalized benzo [b]furans. 13 Until now numerous effective synthetic methodologies for the synthesis 2-substituted benzo [b]furans have been reported. Typical synthetic protocols for 2-substituted benzo [b]furans include transition-metal-catalyzed (such as Pt, 14 Pd, 15 Au/Ag, 16 Au, 17 Rh, 18 Ir, 19 Zn, 20 and Cu 21 ) cyclization of o-alkynylphenols or o-allylphenols, transition-metalcatalyzed (such as Pd, 22 Cu, 23 and Fe 24 ) coupling and cyclization of o-halophenols with alkynes, transition-metal-catalyzed 2-benzo [b]furanylboronic acid or 2-benzo [b]furanyl dimethyl silanolate coupling with aryl halides, 25 and 2halobenzo [b]furan coupling with organometallic nucleophiles. 26 Transition-metal-free synthesis of 2-substituted benzo [b]furans include use of base 27 and by photochemical 28 or oxidative 7a,29 [3,3] sigmatropic rearrangement of Ntrifluoroacetylene hydroxylamines, 30 and the intramolecular Wittig reaction. 31 Despite these efforts the reported alternative methods for the synthesis of 2-substituted benzo [b]furans, in most cases, generally suffer from one or more drawbacks such as requirement of restrictive functional group and co-catalyst, limited substrate scope, multistep synthesis, and poor chemoselectivity, etc. Therefore, the development of more efficient and atom economical approaches for the preparation of 2-substituted benzo [b]furans remains as a desirable work. Among the reported synthetic methodologies for 2substituted benzo [b]furans, the metal-catalyzed 2-halobenzo [b]furan coupling with organometallic nucleophiles is other phosphine ligands, Davephos and PCy 3 did not provide satisfactory results. Solvents were then screened under the model reaction conditions, and the results are summarized in Table 1 (entries 9-11). The coupled product 3aa could not be obtained in DMF. Hexane was suitable for this reaction since it gave higher yield. To our delight, when the loading of PdCl 2 was decreased from 5 to 3 mol%, the yield of coupled product 3aa increased from 64 to 66%, and the selectivity of coupled product 3aa increased from 72:28 to 91:9 (entries 9, 11). To further study the reactivity and product selectivity, other parameters of the reaction conditions were optimized ( Table 2). The effect of the amount of diethylphenylaluminum (1a) was also investigated. When the PhAlEt 2 (1a) loading was increased from 0.8 mmol to 1.0 mmol, the yield and selectivity of coupled product 3aa increased from 66% to 77% and 91:9 to 92:8, respectively (Table 1, entry 11;  Table 2, entry 1). However, when the PhAlEt 2 (1a) loading was increased from 1.0 mmol to 1.2 mmol, the yield and selectivity of coupled product 3aa were unchanged (Table 2, entries 1 and 2). While, excellent selectivity (3aa:4aa = 92:8) and good yield of coupled product 3aa (84%) were obtained when the reaction time was extended to 5 hours (Table 2, entry 1). When the ratio of PdCl 2 and XantPhos was R' PdCl 2 (2-3 mol%) XantPhos (4-6 mol%) K 2 CO 3 (4.0 equiv.) or TMEDA (1 equiv.) hexane, toluene, or DCE (3 mL
The reaction was found to be effective in gram-scale synthesis, which indicated its potential for practical application (Scheme 2). 2-Subtitutedbenzo [b]furans 3ah and 6ah were synthesized in 0.93-1.09 grams using this methodology.
1 H NMR and 13 CNMR spectra were recorded on a Varian 400 MHz spectrometer. The chemical shifts are reported relative to TMS. Analytical TLC was performed on silica 60F-254 plates. Flash column chromatography was carried out on silica gel (200-400 mesh). HRMS were recorded on a Bruker Micro TOF spectrometer equipped with an ESI ion source. All reactions were carried out under N 2 atmosphere. Chemical reagents and solvents were purchased from Adamas-beta, Aldrich, and XPKchem, and were used without further purification with the exception of the following reagents: THF, Et 2 O, and toluene were distilled from Na under N 2 . DCE was distilled from CaH 2 under N 2 . Diethylphenylaluminum (1a) and dimethylarylaluminums 1b-h reagents were prepared according to literature procedures 36b,i,37 [see also Supporting Information (SI)]. Compounds of alkynylaluminum reagents 5a-f were synthesized according to literature procedures 36j,k (see also SI). The preparation of 2-bromobenzo [b]furans 2 is described in SI. Purification of reaction products was carried out by flash chromatography.

Coupling Reaction of 2-Halobenzo[b]furans with Arylaluminums; General Procedure
Under a dry N 2 atmosphere, to a mixture of PdCl 2 (0.0026 g, 0.015 mmol), XantPhos (0.0174 g, 0.03 mmol), and K 2 CO 3 (0.276 g, 2.0 mmol) in a reaction vessel was added an arylaluminum 1 (1.0 mmol) in hexane (3 mL) followed by the addition of the corresponding 2halobenzo [b]furan 2 (0.50 mmol). The resulting solution was stirred at 60 °C for 5 h. After completion of the reaction, the mixture was diluted with sat. aq NH 4 Cl (5 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (anhyd Na 2 SO 4 ), filtered, and evaporated under vacuum. The residue was subjected to flash column chromatography on silica gel (hexane or EtOAc or hexane) to afford the corresponding coupled product 3.

Coupling Reaction of 2-Halobenzo[b]furans with Alkynylaluminums; General Procedure
Under a dry N 2 atmosphere, to a mixture of PdCl 2 (0.0013 g, 0.01 mmol), XantPhos (0.0116 g, 0.02 mmol), and TMEDA (1 equiv) in a reaction vessel was added an alkynylaluminum 5 (0.80 mmol) in toluene (3 mL) followed by the addition of the corresponding 2-halidebenzo [b]furan 2 (0.50 mmol). The resulting solution was stirred at 60°C for 4 h. After completion of the reaction, the mixture was diluted with sat. aq NH 4 Cl (5 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (anhyd Na 2 SO 4 ), filtered, and evaporated under vacuum. The residue was subjected to flash column chromatography on silica gel (hexane or EtOAc and hexane) to afford the corresponding coupled product 6.

Coupling Reaction of 2-Halobenzo[b]furans with Alkylaluminums; General Procedure
Under a dry N 2 atmosphere, to a mixture of PdCl 2 (0.0013 g, 0.01 mmol) and XantPhos (0.0116 g, 0.02 mmol) in a reaction vessel was added an alkenylaluminum 7 (0.60 mmol) in DCE (3 mL) followed by the addition of the corresponding 2-halidebenzo [b]furan 2 (0.50 mmol). The resulting solution was stirred at 60 °C for 4 h. After completion of the reaction, the mixture was diluted with sat. aq NH 4 Cl (5 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried (anhyd Na 2 SO 4 ), filtered, and evaporated under vacuum. The residue was subjected to flash column chromatography on silica gel (hexane or EtOAc and hexane) to afford the corresponding coupled product 8.