To a suspension of 2-chloro-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine hydrochloride (4.03 g, 18.39 mmol) in DCM (100 mL), 2 M aq Na2CO3 (100 mL) was added. After stirring for 30 min, the mixture was diluted with brine (200 mL). The products were extracted twice with DCM. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. A suspension of the residue (3.25 g), 5-isopropyl-2-methylphenyl trifluoromethanesulfonate (11.42 g, 40.5 mmol), Pd2(dba)3.CHCl3 adduct (0.762 g, 0.736 mmol), rac-BINAP (0.945 g, 1.471 mmol) and Cs2CO3 (17.98 g, 55.2 mmol) in toluene (17 mL) and t-butanol (3 mL) was allowed to stir at 90° C. for 23 h under argon. The reaction was cooled to rt, and diluted with EtOAc and brine. The products were extracted three times with EtOAc. The combined organic layer was dried over Na2SO4, and filtered. The filtrate was added to 60 g of silica gel and then concentrated. The residue was washed with EtOAc on a funnel, and then the filtrate was concentrated. The residue was purified by flash column chromatography on 330 g of silica gel (with 25 g pre-column; eluent: heptane/EtOAc=100:0 to 80:20) to give the desired product along with 18 mol % of Carvacrol (2.97 g). The mixture was purified by flash column chromatography on 55 g of NH-modified silica gel (with 20 g of aminopropyl-modified silca gel as pre-column; eluent: heptane/EtOAc=100:0 to 90:10) to give 2-chloro-6-(5-isopropyl-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine (2.50 g) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.16 (d, J=7.83 Hz, 1 H), 6.99-7.00 (m, 2 H), 6.92-6.95 (m, 1 H), 3.98 (s, 2 H), 3.28 (t, J=5.81 Hz, 2 H), 3.12 (br t, J=5.68 Hz, 2 H), 2.84-2.94 (m, 1 H), 2.29 (s, 3 H), 2.20 (s, 3 H), 1.26 (d, J=6.82 Hz, 6 H); MS (ESI+) m/z 315.34 (M+H)+.
