In a sealable reaction vial, ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (180.0 mg, 0.5260 mmol) and a stir pea were azeotroped with toluene 3× and dried under high vacuum overnight. To the vial was added bis(tri-t-butylphosphine)palladium(0) (26.88 mg, 0.05260 mmol). Vial was evacuated and then back-filled with argon 2×, at which time was added via syringe 4-chlorobenzylzinc chloride as a 0.50 M solution in tetrahydrofuran (3.682 mL, 1.841 mmol). The reaction was heated with stirring at 60° C. for 2 h. Reaction was cooled to room temperature and then diluted with EtOAc and sat. aq. NH4Cl. Mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer extracted 2× with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered through a pad of Celite, and concentrated in vacuo to afford a yellow oil. The residue was dissolved in DCM and loaded onto 40 g ISCO column (gradient elution: 0-25% EtOAc/hexanes) to afford ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (92 mg, 43.6%) as a yellow solid. LC/MS: (AA) ES− 386, 388; 1H NMR (400 MHz, DMSO) δ 7.38-7.33 (m, 2H), 7.22 (m, 2H), 6.80-6.76 (m, 1H), 4.40 (s, 2H), 4.34-4.24 (m, 4H), 3.80 (dd, J=5.4, 5.4, 2H), 2.52 (dd, J=2.2, 5.0, 2H), 1.26 (dd, J=7.1, 7.1, 3H).
