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

HRID 2285375Notes

Reaction equation

HRID 2285375 reaction equation
[C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]([C:9]([CH3:15])([CH:13]=[CH2:14])[C:10]([OH:12])=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25]([C@H:29]([O:31][C:32](=[O:34])[CH3:33])[CH3:30])=[N:26]2)=[CH:21][CH:20]=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:32]([O:31][C@@H:29]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][C:19](/[CH:14]=[CH:13]/[C:9]([CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH3:8])([CH3:15])[C:10]([OH:12])=[O:11])=[CH:20][CH:21]=2)[N:26]=1)[CH3:30])(=[O:34])[CH3:33]

Participants

7

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 4594378Bis(cyclohexylmethyl)amineHCID 86709645acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl esterHCID 867096682-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acid

Product 1

HCID 89945083(E)-4-[2-((R)-1-Acetoxy-ethyl)-quinolin-7-yl]-2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acidYield 17%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Procedure

A solution of acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (555.4 mg, 1.888 mmol), 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acid (488.0 mg, 1.888 mmol), palladium(II)acetate (85 mg, 0.378 mmol), tri(o-tolyl)phosphine (115 mg, 0.378 mmol) and N,N-dicyclohexylmethylamine (1.0 mL, 4.720 mmol) in anhydrous 1,4-dioxane (15 mL) was heated at reflux for 2 h. After cooling to warm temperature the reaction was quenched with hydrochloric acid (1 M, 30 mL). The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (252.7 mg, 28%) as a yellow solid along with a 1:3 mixture of 2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acid and acetic acid (R)-1-(7-bromo-quinolin-2-yl)-ethyl ester (474.6 mg) which was dissolved in anhydrous 1,4-dioxane (10 mL), treated with palladium(II)acetate (85 mg, 0.378 mmol), tri(o-tolyl)phosphine (115 mg, 0.378 mmol) and N,N-dicyclohexylmethylamine (1.0 mL, 4.720 mmol) and heated at reflux for 5 h. After cooling to room temperature the mixture was quenched with hydrochloric acid (1 M, 20 mL). The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (149.6 mg, 17%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.12 (s, 3H), 0.15 (s, 3H), 0.93 (s, 9H), 1.25 (d, J=6.0 Hz, 3H), 1.69 (d, J=6.7 Hz, 3H), 2.18 (s, 3H), 2.51 (s, 3H), 4.14 (q, J=6.2 Hz, 1H), 6.08 (q, J=6.7 Hz, 1H), 6.74 (ABq, ΔδAB=0.12, JAB=16.7 Hz, 2H), 7.44 (d, J=8.5 Hz, 1H), 7.64-7.70 (m, 1H), 7.76 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 8.12 (d, J=8.5 Hz, 1H). LCMS (m/z) 472.2 [M+H], Tr=3.61 min.

Workup

  1. temperatureheated
  2. temperatureat reflux for 5 h
  3. customwas quenched with hydrochloric acid (1 M, 20 mL)
  4. extractionThe aqueous layer was extracted with ethyl acetate (2×)
  5. dry with materialThe combined organics were dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. customthe volatiles were removed in vacuo
  8. customThe residue was purified by silica gel chromatography
  9. washeluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:1

Sources & evidence

ORD record
ord-aa84cc214bd34ca189cef6acad16a486
Source dataset
uspto-grants-2015_09
Patent number
US09145441B2

Reaction notes

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