FC1C(C)=CC(O)=C(C=1)C=O.C([O-])([O-])=O.[Cs+].[Cs+].BrCC#N.[F:22][C:23]1[C:32]([CH3:33])=[CH:31][C:26]([O:27][CH2:28][C:29]#[N:30])=[C:25]([CH:34]=O)[CH:24]=1>C(#N)C>[F:22][C:23]1[C:32]([CH3:33])=[CH:31][C:26]2[O:27][C:28]([C:29]#[N:30])=[CH:34][C:25]=2[CH:24]=1To a solution of 5-fluoro-2-hydroxy-4-methylbenzaldehyde (500 mg, 3.24 mmol) in 10.5 ml of acetonitrile in a microwave vial was added Cs2CO3 (1.268 g, 3.885 mmol), followed by 2-bromoacetonitrile (271 ul, 3.885 mmol). The reaction mixture was stirred at room temperature for 1 hr. LC/MS showed that all the starting material was converted to ring opened intermediate, 2-(4-fluoro-2-formyl-5-methylphenoxy)acetonitrile. LCMS retention time=1.19 minutes (R×NMON-Acidic:ZQ12); MS (m+1)=194.1. Then, the reaction vial was sealed, and the mixture was heated to 150° C. on microwave for 20 min. This reaction was repeated 20 times. The combined reaction mixture was filtered, washed with acetonitrile, the filtrate was concentrated. The residue was purified by silica gel flash chromatography (100% heptane-10% ethyl acetate/heptane) to give 5-fluoro-6-methylbenzofuran-2-carbonitrile (5.55 g). 1H NMR (400 MHz, DMSO-d6) δ 2.38 (d, J=2.2 Hz, 3H) 7.62 (d, J=9.3 Hz, 1H) 7.72 (d, J=6.0 Hz, 1H) 8.04 (d, J=1.0 Hz, 1H).
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