4-Methoxy-alpha-toluenethiol → Ethyl 2-fluoro-3-((4-methoxybenzyl)thio)benzoate

HRID 522769Notes

Reaction equation

HRID 522769 reaction equation
Br[C:2]1[C:3]([F:13])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][SH:23])=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.CCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[F:13][C:3]1[C:2]([S:23][CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]

Participants

8

Reactant 3

HCID 804074-Methoxy-alpha-toluenethiolHCID 81531DiisopropylethylamineHCID 17832538Ethyl 3-bromo-2-fluorobenzoate

Product 1

HCID 66764575Ethyl 2-fluoro-3-((4-methoxybenzyl)thio)benzoateYield 88%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8058HexaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

1,4-dioxane (250 mL) was degassed by purging with N2 gas for 30 min and to this, were added a solution of compound A2 (13.2 g, 53.4 mmol) in 1,4-dioxane (50 mL; degassed), (4-methoxyphenyl)methanethiol (PMBSH) (8.2 g, 53.4 mmol), xantphos (1.54 g, 2.66 mmol), diisopropyl ethyl amine (19.6 mL, 106.8 mmol) and Pd2(dba)3 (1.22 g, 1.33 mmol) at RT. The reaction mixture was heated to 90° C. and stirred for 2 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with hexane (450 mL) and stirred at RT for 15 min. The resultant solution was filtered through celite and washed with hexane (100 mL). The filtrate was washed water (250 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified through silica gel column chromatography using 3-4% EtOAc/Hexanes to afford compound A3 (15 g, 88%) as pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.78-7.74 (m, 1H), 7.43-7.39 (m, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.07-7.04 (m, 1H), 6.80 (d, J=8.0 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 4.08 (s, 2H), 3.78 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LC-MS (ESI): 89.7%; m/z 318.9 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.22 min; 5 mM NH4OAc: ACN; 0.8 mL/min).

Workup

  1. custom1,4-dioxane (250 mL) was degassed
  2. customby purging with N2 gas for 30 min
  3. customafter completion of the reaction
  4. stirringstirred at RT for 15 min
  5. filtrationThe resultant solution was filtered through celite
  6. washwashed with hexane (100 mL)
  7. washThe filtrate was washed water (250 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customto obtain the crude
  12. customThe crude was purified through silica gel column chromatography

Sources & evidence

ORD record
ord-05bbf9764165450280cf5f253a67ba8d
Source dataset
uspto-grants-2016_05
Patent number
US09334261B2

Reaction notes

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