Tri-o-tolylphosphine → (E)-(R)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoic acid

HRID 2285348Notes

Reaction equation

HRID 2285348 reaction equation
[CH3:1][C@:2]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([CH:6]=[CH2:7])[C:3]([OH:5])=[O:4].Br[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][C:23]([C@H:27]([O:29][C:30](=[O:32])[CH3:31])[CH3:28])=[N:24]2)=[CH:19][CH:18]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:30]([O:29][C@@H:27]([C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:26][C:17](/[CH:7]=[CH:6]/[C@:2]([CH3:1])([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:13])[CH3:14])[C:3]([OH:5])=[O:4])=[CH:18][CH:19]=2)[N:24]=1)[CH3:28])(=[O:32])[CH3:31]

Participants

7

Reactant 4

HCID 80271Tri-o-tolylphosphine3×HCID 4594378Bis(cyclohexylmethyl)amineHCID 86709643(R)-2-Methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoic acidHCID 86709645acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester

Product 1

HCID 86709644(E)-(R)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoic acidYield 85.3%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalyst3×HCID 312751,4-DioxaneSolvent

Procedure

A solution of (R)-2-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-but-3-enoic acid (214.1 0.728 mmol), acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (167.7 mg, 0.728 mmol), palladium(II)acetate (33.0 mg, 0.146 mmol), tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol) and N,N-dicyclohexylmethylamine (390 μL, 1.820 mmol) in anhydrous 1,4-dioxane (10 mL) was heated at reflux for 3 h, after which palladium(II)acetate (33.0 mg, 0.146 mmol) and tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol) were added. After 1.5 h, the heating was stopped and the reaction was allowed to stand at room temperature overnight. The mixture was then treated with palladium(II)acetate (33.0 mg, 0.146 mmol) and tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol). After stirring at reflux for 3 h, the mixture was cooled to room temperature, quenched with hydrochloric acid (1 M, 10 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 25 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (275.5 mg, 85%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.04 (s, 9H), 1.02 (dd, J=9.1, 7.3 Hz, 2H), 1.50 (s, 3H), 1.69 (d, J=6.7 Hz, 3H), 2.18 (s, 3H), 3.59-3.76 (m, 4H), 6.07 (q, J=6.7 Hz, 1H), 6.67 (ABq, ΔδAB=0.15, JAB=16.3 Hz, 2H), 7.44 (d, J=8.2 1H), 7.62 (dd, J=8.5, 1.3 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 8.05 (s, 1H), 8.12 (d, J=8.5 Hz, 1H). LCMS (m/z) 444.1 [M+H], Tr=3.29 min.

Workup

  1. temperatureat reflux for 3 h
  2. waitto stand at room temperature overnight
  3. temperatureat reflux for 3 h
  4. customquenched with hydrochloric acid (1 M, 10 mL)
  5. extractionThe aqueous layer was extracted with ethyl acetate (2×)
  6. dry with materialdried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. customthe volatiles were removed in vacuo
  9. customThe residue was purified by silica gel chromatography
  10. washeluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1

Sources & evidence

ORD record
ord-99fd35ac31924e9398dc29090bfee6b9
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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