Compound 1a

View in PubChem | MDL Molfile | Chemdraw file

Compound data: 1H NMR

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

MOMCl (1.1 g, 13.6 mmol, 1.5 equiv.) was added to a mixture of 2-iodophenol S1a (2 g, 9.1 mmol, 1 equiv.) and K₂CO₃ (5.0 g, 36.36 mmol, 4 equiv.) in DMF (8 ml). The mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC (Pent/Et₂O: 9/1). The solution was diluted with diethyl ether (100 ml) and 60 ml of water were added. The layers were separated and the aqueous phase was extracted with diethyl ether (3 × 30 ml). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure to afford 1-iodo-2-(methoxymethoxy)benzene S2a (2.4 g, quant). The latter was engaged without further purification in the next step. To a stirred solution of 1-ethynyl-4-methylbenzene (1.2 g, 10.0 mmol, 1.1 equiv.) and S2a (2.4 g, 9.1 mmol, 1.0 equiv.) in triethylamine (90 ml) were added PdCl₂(PPh₃)₂ (126.3 mg, 0.18 mmol, 2 mol%) and CuI (34.3 mg, 0.18 mmol, 2 mol%). The mixture was stirred at 65°C until complete consumption of S2a was observed by TLC (Pent/Et₂O: 9/1). The reaction mixture was cooled to room temperature, diethyl ether was added (50 ml) and the mixture was filtered through a plug of cotton wool. After removal of the solvent, the residue was purified by silica gel chromatography (Pent/Et₂O: 9/1) to afford 1-(methoxymethoxy)-2-(p-tolylethynyl)benzene S3a (2.07 g, 90%). The deprotection of MOM was conducted by addition of aqueous HCl (0.85 ml, 9.0 mmol, 6N) to a solution of S3a (2.07 g, 8.2 mmol) in MeOH (15 ml). The reaction mixture was stirred until the deprotection was completed. The mixture was diluted with water (50 ml) and diethyl ether (30 ml). The layers were separated and the aqueous phase was extracted with diethyl ether (3 × 30 ml). The combined organic layers were washed with brine, dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Pent/Et₂O: 9/1) to afford 1a (1.45 g, 85%) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.45–7.40 (m, 3H), 7.28–7.24 (m, 1H), 7.19–7.17 (m, 2H), 6.98 (bdd, J = 8.4, 1.2 Hz, 1H), 6.90 (td, J = 7.5, 1.2 Hz, 1H), 5.83 (s, 1H), 2.39 (s, 3H).