5-Bromo-1-benzothiophene → 4-Benzo[b]thiophen-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-ol

HRID 402117Notes

Reaction equation

HRID 402117 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])(C)(C)C.[CH3:16][N:17]1[CH2:26][C:25](=[O:27])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1>>[S:9]1[CH:8]=[CH:7][C:6]2[CH:10]=[C:2]([C:25]3([OH:27])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:16])[CH2:26]3)[CH:3]=[CH:4][C:5]1=2.[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:25]3([OH:27])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][N:17]([CH3:16])[CH2:26]3)=[CH:7][C:6]=2[CH:10]=1

Participants

5

Reactant 3

HCID 27765785-Bromo-1-benzothiopheneHCID 106308122-Methyl-2,3-dihydroisoquinolin-4(1H)-oneHCID 178418306HCID 178418306, compound

Product 2

HCID 68993470HCID 68993470, compoundYield 8%HCID 689942574-Benzo[b]thiophen-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-olYield 11%

Conditions

Temperature
-75 °C

Procedure

To a solution of 5-bromobenzothiophene (511 mg, 2.4 mmol) at −75° C., was added t-butyllithium (1.7 M in pentane, 1.6 mL, 2.6 mmol) dropwise. The reaction mixture was stirred at −75° C. for 1 hour. To the resulting dark brown mixture was added 2-methyl-2,3-dihydro-1H-isoquinolin-4-one (323 mg, 2.0 mmol), which was prepared using the method described by Hanna et al., J. Med. Chem., 17(9):1020-1023 (1974), which is hereby incorporated by reference in its entirety. The reaction mixture was stirred for 15 hours with gradual warming up. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by medium pressure silica gel chromatography (10-40% ethyl acetate/hexanes) followed by preparative HPLC afforded 4-(benzo[b]thiophen-5-yl)-2-methyl-1,2,3,4-tetrahydro-isoquinoline-4-ol (65 mg, 11%) and 4-(5-bromobenzo[b]thiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol (58 mg, 8%). 4-(Benzothiophen-5-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 500 MHz) δ 7.81 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.34-7.23 (m, 4H), 7.20 (s, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 3.91 (s, 1H), 3.84 (d, J=15.0 Hz, 1H), 3.53 (d, J=15.0 Hz, 1H), 3.11 (dd, J=11.6, 1.4 Hz, 1H), 2.87 (d, J=11.6 Hz, 1H), 2.50 (s, 3H); ESI MS m/z=296 [M+H]+. 4-(5-Bromobenzothiophen-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline-4-ol: 1H NMR (CDCl3, 300 MHz) δ 7.81 (d, J=1.8 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.18 (d, J=7.3 Hz, 1H), 7.11 (s, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.69 (d, J=15.0 Hz, 1H), 3.48 (d, J=15.0 Hz, 1H), 3.10 (dd, J=11.6, 1.3 Hz, 1H), 2.83 (d, J=11.6 Hz, 1H), 2.47 (s, 3H); ESI MS m/z=374 [M+H]+.

Workup

  1. customwas prepared
  2. stirringThe reaction mixture was stirred for 15 hours
  3. temperaturewith gradual warming up
  4. customThe mixture was quenched with saturated ammonium chloride
  5. extractionextracted with ethyl acetate (3×50 ml)
  6. washThe combined organic extracts were washed with saturated sodium chloride
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by medium pressure silica gel chromatography (10-40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-f769682ff33b466eae3992321fd2f571
Source dataset
uspto-grants-2014_06
Patent number
US08741901B2

Reaction notes

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