Cesium fluoride → (S)-cyclopropyl(2-methyl-5-phenoxy-6-(prop-1-ynyl)-3,4-dihydroquinolin-1(2H)-yl)methanone

HRID 1051720Notes

Reaction equation

HRID 1051720 reaction equation
Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.[F-].[Cs+].[CH2:27]([Sn](CCCC)(CCCC)C#CC)[CH2:28][CH2:29]C>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CC(OC)(C)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].O1CCOCC1>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:2]([C:27]#[C:28][CH3:29])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1

Participants

6

Reactant 3

HCID 25953Cesium fluorideHCID 2733165Tributyl(prop-1-yn-1-yl)stannaneHCID 118086215(S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone

Product 1

HCID 118076000(S)-cyclopropyl(2-methyl-5-phenoxy-6-(prop-1-ynyl)-3,4-dihydroquinolin-1(2H)-yl)methanone

Reagents, catalysts & solvents 2

HCID 66572931HCID 66572931, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
160 °C

Procedure

A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.050 g, 0.13 mmol), RuPhos Precatalyst 3rd generation ((2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate) (0.011 g, 0.01 mmol), cesium fluoride (0.099 g, 0.65 mmol), and tributyl(prop-1-ynyl)stannane (0.107 g, 0.32 mmol) in 1,4-dioxane (4 mL) was heated with microwave irradiation for 1 h at 160° C. The reaction mixture was cooled to room temperature, passed through a short pad of Celite and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 1:5, ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flow rate: 20 mL/min); Detector: UV 220&254 nm. This afforded (S)-cyclopropyl(2-methyl-5-phenoxy-6-(prop-1-ynyl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.011 g, 26%) as a light brown semi-solid. 1H NMR (400 MHz, CD3OD) δ ppm 0.65-0.85 (m, 1H), 1.02-0.87 (m, 2H), 1.03-1.22 (m, 4H), 1.37-1.51 (m, 1H), 1.82 (s, 3H), 1.88-2.03 (m, 1H), 2.07-2.42 (m, 2H), 2.58-2.82 (m, 1H), 4.85-4.72 (m, 1H), 6.78 (d, J=7.80 Hz, 2H) 7.00 (t, J=7.50 Hz, 1H), 7.25-7.31 (m, 4H). MS (ESI, pos. ion) m/z 346 [M+H]+.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. concentrationconcentrated under vacuum
  3. customThe residue was purified via preparative thin layer chromatography (eluting with 1:5, ethyl acetate/petroleum ether)
  4. customThe product was further purified by preparative-HPLC with the following conditions (Waters I)
  5. custommobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% to 100% acetonitrile in 10 min, flow rate: 20 mL/min)

Sources & evidence

ORD record
ord-1596d9b38c5e4f1aa08f3a2d8f31614b
Source dataset
uspto-grants-2016_07
Patent number
US09388161B2

Reaction notes

Loading…