Benzyl mercaptan → (E)-Ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate

HRID 1504460Notes

Reaction equation

HRID 1504460 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12].CCN(C(C)C)C(C)C.[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1.C(OCC)(=O)C.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>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]

Participants

8

Reactant 3

HCID 7509Benzyl mercaptanHCID 81531DiisopropylethylamineHCID 86278419(E)-ethyl 3-(2-amino-5-bromophenyl)acrylate

Product 1

HCID 117740420(E)-Ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylateYield 72.5%

Reagents, catalysts & solvents 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g, 2.29 mol, 1.0 equiv) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L, 8.88 mol, 3.9 equiv, GLR) and degassed with nitrogen for 20 mins. XantPhos (92.9 g, 106 mmol, 0.05 equiv, GLR), and tris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv, Hindustan Platinum) was added to the reaction mixture. The mixture was purged with nitrogen and heated to 80° C. for 30 mins. The reaction was cooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv, Alfa Aesar) was added and the reaction was heated at 80° C. for an additional 4 h. The reaction was cooled to room temperature and diluted with ethyl acetate (4.0 L). The mixture was filtered through celite and the celite bed was washed with ethyl acetate (2×1.0 L). The filtrate was concentrated under reduced pressure to obtain the crude material which was purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%), as yellow solid. TLC solvent system: 30% ethyl acetate in hexanes. Product's Rf: 0.4. MS (ESI, positive ion) m/z; 314.1 (M+1). NMR (400 MHz, DMSO) δ 7.79 (d, J=16.1 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.25-7.17 (m, 5H) 7.10 (dd, J=8.4, 2.1 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.32 (d, J=15.2 Hz, 1H), 5.75 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.01 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).

Workup

  1. customdegassed with nitrogen for 20 mins
  2. customThe mixture was purged with nitrogen
  3. temperatureThe reaction was cooled to RT
  4. temperaturethe reaction was heated at 80° C. for an additional 4 h
  5. temperatureThe reaction was cooled to room temperature
  6. filtrationThe mixture was filtered through celite
  7. washthe celite bed was washed with ethyl acetate (2×1.0 L)
  8. concentrationThe filtrate was concentrated under reduced pressure
  9. customto obtain the crude material which
  10. customwas purified by chromatography (silica gel; mesh size 60-120, elution 0-40% ethyl acetate and petroleum ether)

Sources & evidence

ORD record
ord-35c311f9924a491fb8672631234df0fb
Source dataset
uspto-grants-2015_12
Patent number
US09212182B2

Reaction notes

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