Substitution (Br)

(Aromatic Alcohols)

Examples:

Example 1

The alcohol (A) (2 g, 8.6 mmol), the bromide (B) (0.9 mL, 9.5 mmol), and K2CO3 (1.8 g, 13 mmol) in ACN (40 mL) were stirred at 80 C overnight. The mixture was diluted with H2O and EtOAc. The org layer was separated, dried (MgSO4), and concentrated. The resulting material was purified by Prep LC (450 g silica, 15% EtOAc/heptane) to provide the product. [2.1 g, 84%]

[Patent Reference: WO2015144799, page 183, (18.8 MB)]

Example 2

To a solution of the phenol (B) (25 g, 205 mmol) and the alkyl bromide (A) (57 g, 225 mmol) in ACN (200 mL) was added K2CO3 (85 g, 614 mmol). The reaction mixture was stirred at 80 C for 12 h. After cooling to RT, DCM (50 mL) was added and the mixture was filtered through celite. The filtrate was concentrated and the resulting material was purified by silica gel column chromatography (20:1 PE/EtOAc) to provide the product as a white solid. [36 g, 60%]

[Patent Reference: WO2015140133, page 127, (11.7 MB)]

Example 3

The alkyl bromide (B) (1.48 mL, 11.42 mmol) was added to a solution of the alcohol (A) (1.0 g, 5.71 mmol) and K2CO3 (1.59 g, 11.42 mmol) in DMF (2 mL). The reaction was stirred at 50 C for 1 h, then RT overnight. The mixture was diluted with EtOAc and H2O. The layers were separated and the aq layer was further extracted with EtOAc. The combined organics were washed with H2O (3x), dried (Na2SO4), and concentrated. The crude material was purified by column chromatography (0-50% EtOAc/DCM) to provide the product. [0.506 g, 32%]

[Patent Reference: WO2014110000, page 70, (2.6 MB)]

Example 4

To a solution of the phenol (A) (0.200 g, 1.07 mmol) in acetone (10 mL) was added the alkyl bromide (B) (0.40 g, 1.2 mmol) followed by Cs2CO3 (1.0 g, 3.1 mmol). The mixture was stirred at RT overnight, after which time it was filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography to provide the product. [0.34 g]

[Patent Reference: WO2016014463, page 169, (6.7 MB)]

Example 5

To a mixture of the alcohol (B) (600 mg, 1.4 mmol) and K2CO3 (382 mg, 2.8 mmol) in DMF (5 mL) was added the alkyl bromide (A) (660 mg, 2.8 mmol). The resulting mixture was stirred at 70 C for 3 h. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography (1:10 EtOAc/PE) to provide the product as a colorless oil. [560 mg, 68%]

[Patent Reference: WO2016011390, page 371, (20.2 MB)]

Example 6

To a solution of the phenol (A) (2.0 g, 12.7 mmol) in acetone (30 mL) was added K2CO3 (2.12 g, 15.3 mmol) and the alkyl bromide (B) (2.54 g, 15.2 mmol). The reaction mixture was stirred at reflux for 16 h, after which time the mixture was cooled to RT and concentrated in vacuo. The resulting material was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The org layer was dried (Na2SO4), concentrated, and purified by silica gel column chromatography to provide the product as a yellow liquid. [2.2 g, 71%]

[Patent Reference: WO2014149164, page 336, (23.7 MB)]

Example 7

To a solution of the phenol (B) (7.00 g, 31.8 mmol) in ACN (75 mL) at RT was added K2CO3 (5.28 g, 38.2 mmol) and the alkyl bromide (A) (6.03 mL, 35.0 mmol). The reaction mixture was stirred at RT overnight. The mixture was filtered through a pad of celite and the pad was washed with DCM. The filtrate was concentrated to a volume of 100 mL, then ether and heptane were added. The mixture was concentrated in vacuo to give 12.36 g of impure material as a yellow solid. The material was purified by Prep LC (220 g silica, 0-20% EtOAc/heptane) to provide the product as a white sticky solid. [9.88 g, 88%]

[Patent Reference: WO2015144799, page 85, (18.8 MB)]

Example 8

To a solution of the SM (0.70 g, 3.37 mmol) in dry DMF (15 mL) was added Cs2CO3 (1.21 g, 3.71 mmol). The resulting mixture was stirred at RT for 10 min, after which time bromoethane (0.30 mL, 4.05 mmol) was added and the reaction mixture was stirred at RT overnight. The mixture was then diluted with Et2O (100 mL) and H2O (10 mL). The layers were separated and the org layer was further washed with H2O (2 x 10 mL), brine (20 mL), dried (Na2SO4), and concentrated in vacuo. The resulting crude was purified by silica gel column chromatography (0-25% EtOAc/cyclohexane) to provide the product as a yellow solid. [544 mg, 68%]

[Patent Reference: WO2012112946, page 129, (11.2 MB)]

Example 9

To a solution of the alcohol (B) (427 mg, 2.68 mmol), the alkyl bromide (A) (914 mg, 4.02 mmol), and DMSO (10 mL) was added K2CO3 (1.48 g, 10.7 mmol). After stirring at RT for 16 h, the mixture was diluted with H2O and extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting crude material was purified by MPLC (10% EtOAc/hexane) to provide the product as a colorless solid. [604 mg]

[Patent Reference: WO2015163936, page 28, (1.8 MB)]

Example 10

The phenol (B) (0.873 g, 3.92 mmol) was dissolved in DMF (7.84 mL). K2CO3 (0.542 g, 3.92 mmol) was added, followed by bromoacetonitrile (A) (0.300 mL, 4.31 mmol). The reaction was stirred at RT overnight, after which time it was diluted with EtOAc and washed with H2O. The aq layer was extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated to provide the product as a white solid. [0.990 g, 96%]

[Patent Reference: WO2014201173, page 213, (19.7 MB)]