Methanol → benzyl 3-(2-methoxy-2-oxoacetyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

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To a suspension of 6-((benzyloxy)carbonyl)-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid (intermediate 9) (0.1240 g, 0.298 mmol) in CH2Cl2 with of DMF (2 mL) was added 2M (CH2Cl2) oxalyl chloride (0.298 mL, 0.595 mmol) and the solution stirred at room temperature. After 1 h, the mixture was concentrated and azeotroped with toluene 3 times to remove unreacted oxalyl chloride. The residue was taken up in CH2Cl2 (2.0 mL). iPr2NEt (0.156 mL, 0.893 mmol) and 1-(cyanomethyl)tetrahydro-1H-thiophen-1-ium, bromide salt (0.081 g, 0.387 mmol) were added and the solution stirred at room temperature for 20 h. The mixture was washed with water, then dried (Na2SO4), filtered and concentrated to give an amber oil. The oil was dissolved in MeOH (4 mL). a solution of oxone (0.366 g, 0.595 mmol) dissolved in water (1.5 mL) was added. The resulting suspension was stirred at room temperature for 2 h. Methanol was concentrated was removed under vacuum and the remaining solution extracted with EtOAc (3×'s). The organic layers were combined and washed with brine, dried (Na2SO4), filtered and concentrated. The resulting brown residue was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane) to provide benzyl 3-(2-methoxy-2-oxoacetyl)-2-methyl-4-(p-tolyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (0.063 g, 32% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.14-7.51 (m, 7H), 6.92-7.11 (m, 2H), 5.13 (br. s., 2H), 4.28-4.52 (m, 2H), 3.44 (s, 3H), 3.25-3.38 (m, 2H), 3.11 (br. s., 2H), 2.50-2.63 (m, 3H), 2.41 (s, 3H). LCMS (M+H) calcd for C27H27N2O5: 459.19. found: 459.3.

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