Reaction Steps
A 25 mL glass microwave tube was charged with potassium phosphate tribasic (3.00 g, 13.05 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′,-tri-isopropyl-1,1′-biphenyl (Strem Chemicals, Newburyport, Mass., 83 mg, 0.174 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, Newburyport, Mass., 80 mg, 0.087 mmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (Acros Organics, New Jersey, 971 mg, 4.35 mmol) followed by 5-chloro-2-nitroanisole (Sigma Aldrich, 816 mg, 4.35 mmol). The solids were purged with argon and treated with 1,4-dioxane (12 mL) and water (4 mL), scaled and heated at 110° C. in a heating block for 1 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (3×30 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified on the ISCO Combiflash RF (80 g Thomson SingleStep column, using a gradient of 0-20% MeOH in DCM) affording 4-(3-methoxy-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (19a; 970 mg, 3.91 mmol, 90% yield) as a rust-brown solid which crystallized upon standing. m/z (ESI, +ve ion) 249.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (1H, d, J=8.4 Hz), 6.99-7.08 (2H, m), 6.17-6.24 (1H, m), 3.97 (3H, s), 3.15 (2H, q, J=2.8 Hz), 2.65-2.74 (2H, m), 2.53-2.62 (2H, m), 2.38-2.46 (3H, m). In a 50 mL glass reactor, 4-(3-methoxy-4-nitrophenyl)-1-methyl-1,2,3,6-tetrahydropyridine (940 mg, 3.79 mmol) was treated with palladium hydroxide (20 wt % Pd, dry basis, on wet carbon, degussa type e101 ne/w, 266 mg, 0.38 mmol) and anhydrous EtOH (20 mL). The reactor was purged with hydrogen (5×) and allowed to stir under 50 psi hydrogen at RT for 4 h. The reaction mixture was filtered through a 0.45 urn acrodisc to remove the catalyst residues washing with MeOH and concentrated to dryness under high vacuum affording 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (19b; 830 mg, 3.77 mmol, 99% yield) as a yellow crystalline solid. m/z (ESI, +ve ion) 221.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 6.56-6.74 (3H, m), 3.76-3.89 (3H, m), 3.54-3.76 (2H, m), 2.97 (2H, d, J=11.2 Hz), 2.34-2.47 (1H, m), 2.23-2.34 (3H, 1.95-2.12 (2H, m), 1.70-1.90 (4H, m).
