Reaction #710585

Reaction equation

NH4Cl

2-Bromopropane

5-chloro-7-iodo-quinolin-8-ol

K2CO3

→

5-chloro-7-iodo-8-isopropoxy-quinoline

Yield 93.3%

Solvents

DMSO

Conditions

Workup

1. 1
   Extractionthe mixture extracted with dichloromethane (10 mL×3)
2. 2
   Concentrationconcentrated
3. 3
   workup.ADDITIONDiethyl ether (40 mL) was added to the residue
4. 4
   Washthe resulting mixture washed successively with 2 N NaOH, H2O and brine
5. 5
   Dryingdried (Na2SO4)

Procedure

2-Bromopropane (0.46 mL, 4.90 mmol) was added into a stirred mixture of the 5-chloro-7-iodo-quinolin-8-ol (1.00 g, 3.27 mmol), K2CO3 (1.86 g, 13.5 mmol) and DMSO (10 mL). After 16 h at RT, saturated NH4Cl (10 mL) was added and the mixture extracted with dichloromethane (10 mL×3). The extracts were combined and concentrated. Diethyl ether (40 mL) was added to the residue and the resulting mixture washed successively with 2 N NaOH, H2O and brine, and dried (Na2SO4). Subsequent column chromatography on silica (ethyl acetate/hexane, 1:1) afforded 5-chloro-7-iodo-8-isopropoxy-quinoline 5 as a solid (1.06 g, 93%). 5: 1H NMR (CDCl3): δ 8.93 (dd, J=1.5 and 4.2, 1H), 8.52 (dd, J=1.5 and 8.4, 1H), 7.98 (s, 1H), 7.53 (dd, J=4.2 and 8.4, 1H), 5.38 (m, 1H), 1.43 (d, J=6.0, 6 H). To a stirred mixture of 5-chloro-7-iodo-8-isopropoxy-quinoline 5 (200 mg, 0.58 mmol), phenylboronic acid (77 mg, 0.62 mmol), 2 N Na2CO3 (7.2 mL), EtOH (1.2 mL) and benzene (6 mL) was added, under a blanket of argon, Pd(PPh3)4 (20 mg). The mixture was stirred under reflux for 16 h, cooled and concentrated. This provided, after column chromatography on silica (ethyl acetate/hexane, 1:9), 5-chloro-7-phenyl-8-isopropoxy-quinoline as a yellow solid. To a stirred solution of the 8-isopropoxy-quinoline (0.339 mmol) in dichloromethane (2 mL) at −78° C. was added BCl3 (1.36 mL of a 1 M solution in dichloromethane, 1.36 mmol). After 2 h, the reaction mixture was allowed to warm to RT and stirred for a further 2 h. MeOH (5 mL) was added and the mixture was concentrated to dryness. This process was repeated four times. Further washing of the remaining residue with diethyl ether (2 mL×3) provided K1 in 91% yield. Data in Table 4.

Source