4-(2-chloroethoxy)-3-methoxybenzaldehyde

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of vanillin (10.00 g, 65.7 mmol), K2CO3 (45.4 g, 329 mmol), 1,2-dichloroethane (104 mL, 1.31 mol), and DMF (300 mL) was stirred at 65-70° C. for 16 h. The dichloroethane was evaporated and the remaining slurry was poured onto ice. The oil that separated was extracted with Et2O (×4) and EtOAc (×3). The combined extracts were washed with water (×3), dried (Na2SO4 /MgSO4), and evaporated to give a clear oil that solidified upon trituration with hexanes. Crystallization from Et20 gave 4-(2-chloroethoxy)-3-methoxybenzaldehyde (12.04 g, 85%) as white needles, mp 60-61° C. 1H NMR (CDCl3) δ 9.87 (s, 1 H, CHO), 7.46 (dd, J=8.0, 2.0 Hz, 1 H, H-6), 7.43 (d, J=2.0 Hz, 1 H, H-5), 6.99 (d, J=8.0 Hz, 1 H, H-2), 4.36 (t, J=6.1 Hz, 2 H, OCH2), 3.94 (s, 3 H, OCH3), 3.89 (t, J=6.1 Hz, 2 H, CH2Cl); 13C NMR δ 190.8 (CHO), 153.9 (C-4), 150.0 (C-3), 130.8 (C-1), 126.3 (C-6), 112.3 (C-2), 109.8 (C-5), 68.9 (OCH2), 56.0 (OCH3), 41.2 (CH2Cl). The dichloroethane was evaporated the remaining slurry was poured onto ice The oil that separated was extracted with Et2O (×4) and EtOAc (×3) The combined extracts were washed with water (×3) dried (Na2SO4 /MgSO4) evaporated to give a clear oil that Crystallization from Et20

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Fuming nitric acid (10 mL) is added dropwise to a −40° C. suspension of 5.00 g (23.36 mmol) of 4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et. al., J. Med. Chem., 42(4), 649-658, 1999) in 23 mL of 1,2-dichloroethane. The reaction mixture is slowly allowed to warm to −10° C. The mixture is poured onto 300 mL of ice water and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the pale yellow solid is collected by filtration to provide 2.43 g (40%) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp 148-150° C. extracted with ethyl acetate The organic layer is dried over magnesium sulfate filtered concentrated in vacuo Diethyl ether is added to the residue the pale yellow solid is collected by filtration

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Fuming nitric acid (10 mL) is added dropwise to a −40° C. suspension of 5.00 g (23.36 mmol) of 4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et. al., J. Med. Chem., 42(4), 649-658, 1999) in 23 mL of 1,2-dichloroethane. The reaction mixture is slowly allowed to warm to −10° C. The mixture is poured onto 300 mL of ice water and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the pale yellow solid is collected by filtration to provide 2.43 g (40%) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp 148-150° C. extracted with ethyl acetate The organic layer is dried over magnesium sulfate filtered concentrated in vacuo Diethyl ether is added to the residue the pale yellow solid is collected by filtration

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of vanillin (10.00 g, 65.7 mmol), K2CO3 (45.4 g, 329 mmol), 1,2-dichloroethane (104 mL, 1.31 mol), and DMF (300 mL) was stirred at 65-70° C. for 16 h. The dichloroethane was evaporated and the remaining slurry was poured onto ice. The oil that separated was extracted with Et2O (×4) and EtOAc (×3). The combined extracts were washed with water (×3), dried (Na2SO4 /MgSO4), and evaporated to give a clear oil that solidified upon trituration with hexanes. Crystallization from Et20 gave 4-(2-chloroethoxy)-3-methoxybenzaldehyde (12.04 g, 85%) as white needles, mp 60-61° C. 1H NMR (CDCl3) δ 9.87 (s, 1 H, CHO), 7.46 (dd, J=8.0, 2.0 Hz, 1 H, H-6), 7.43 (d, J=2.0 Hz, 1 H, H-5), 6.99 (d, J=8.0 Hz, 1 H, H-2), 4.36 (t, J=6.1 Hz, 2 H, OCH2), 3.94 (s, 3 H, OCH3), 3.89 (t, J=6.1 Hz, 2 H, CH2Cl); 13C NMR δ 190.8 (CHO), 153.9 (C-4), 150.0 (C-3), 130.8 (C-1), 126.3 (C-6), 112.3 (C-2), 109.8 (C-5), 68.9 (OCH2), 56.0 (OCH3), 41.2 (CH2Cl). The dichloroethane was evaporated the remaining slurry was poured onto ice The oil that separated was extracted with Et2O (×4) and EtOAc (×3) The combined extracts were washed with water (×3) dried (Na2SO4 /MgSO4) evaporated to give a clear oil that Crystallization from Et20

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Fuming nitric acid (10 mL) is added dropwise to a −40° C. suspension of 5.00 g (23.36 mmol) of 4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et. al., J. Med. Chem., 42(4), 649–658, 1999) in 23 mL of 1,2-dichloroethane. The reaction mixture is slowly allowed to warm to −10° C. The mixture is poured onto 300 mL of ice water and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the pale yellow solid is collected by filtration to provide 2.43 g (40%) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp 148–150° C. extracted with ethyl acetate The organic layer is dried over magnesium sulfate filtered concentrated in vacuo Diethyl ether is added to the residue the pale yellow solid is collected by filtration

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Fuming nitric acid (10 mL) is added dropwise to a −40° C. suspension of 5.00 g (23.36 mmol) of 4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et. al., J. Med. Chem., 42(4), 649–658, 1999) in 23 mL of 1,2-dichloroethane. The reaction mixture is slowly allowed to warm to −10° C. The mixture is poured onto 300 mL of ice water and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the pale yellow solid is collected by filtration to provide 2.43 g (40%) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp 148–150° C. extracted with ethyl acetate The organic layer is dried over magnesium sulfate filtered concentrated in vacuo Diethyl ether is added to the residue the pale yellow solid is collected by filtration

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Fuming nitric acid (10 mL) is added dropwise to a −40° C. suspension of 5.00 g (23.36 mmol) of 4-(2-chloroethoxy)-3-methoxybenzaldehyde (Milbank, J. B. J., et. al., J. Med. Chem., 42(4), 649-658, 1999) in 23 mL of 1,2-dichloroethane. The reaction mixture is slowly allowed to warm to −10° C. The mixture is poured onto 300 mL of ice water and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the pale yellow solid is collected by filtration to provide 2.43 g (40%) of 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzaldehyde, mp 148-150° C. extracted with ethyl acetate The organic layer is dried over magnesium sulfate filtered concentrated in vacuo Diethyl ether is added to the residue the pale yellow solid is collected by filtration

Conditions: temp:67.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of vanillin (10.00 g, 65.7 mmol), K2CO3 (45.4 g, 329 mmol), 1,2-dichloroethane (104 mL, 1.31 mol), and DMF (300 mL) was stirred at 65-70° C. for 16 h. The dichloroethane was evaporated and the remaining slurry was poured onto ice. The oil that separated was extracted with Et2O (×4) and EtOAc (×3). The combined extracts were washed with water (×3), dried (Na2SO4 /MgSO4), and evaporated to give a clear oil that solidified upon trituration with hexanes. Crystallization from Et20 gave 4-(2-chloroethoxy)-3-methoxybenzaldehyde (12.04 g, 85%) as white needles, mp 60-61° C. 1H NMR (CDCl3) δ 9.87 (s, 1 H, CHO), 7.46 (dd, J=8.0, 2.0 Hz, 1 H, H-6), 7.43 (d, J=2.0 Hz, 1 H, H-5), 6.99 (d, J=8.0 Hz, 1 H, H-2), 4.36 (t, J=6.1 Hz, 2 H, OCH2), 3.94 (s, 3 H, OCH3), 3.89 (t, J=6.1 Hz, 2 H, CH2Cl); 13C NMR δ 190.8 (CHO), 153.9 (C-4), 150.0 (C-3), 130.8 (C-1), 126.3 (C-6), 112.3 (C-2), 109.8 (C-5), 68.9 (OCH2), 56.0 (OCH3), 41.2 (CH2Cl). The dichloroethane was evaporated the remaining slurry was poured onto ice The oil that separated was extracted with Et2O (×4) and EtOAc (×3) The combined extracts were washed with water (×3) dried (Na2SO4 /MgSO4) evaporated to give a clear oil that Crystallization from Et20