Cesium carbonate → 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile

HRID 406727Notes

Reaction equation

HRID 406727 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[O:29]=[C:30]1[NH:35][CH:34]=[C:33](B(O)O)[CH:32]=[CH:31]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:26][C:23]([CH3:27])([CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[CH:31][C:30](=[O:29])[NH:35][CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[C:24]#[N:25]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 467387646-Hydroxypyridine-3-boronic acidHCID 596356493-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile

Product 1

HCID 596356372,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrileYield 94.3%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (208 mg, 0.47 mmol) in 1,4-dioxane (5 mL) were added 6-oxo-1,6-dihydropyridin-3-ylboronic acid (98 mg, 1.5 equiv), 2.0 M aq Cs2CO3 solution (500 μL), and Pd(dppf)Cl2 (20 mg, 0.06 equiv). The mixture was degassed and refilled with N2 gas 3 times, before being heated to 90° C. (oil bath) for 3 h. LC-MS found the reaction was complete. The mixture was cooled to rt, diluted with EtOAc (25 mL), and washed with water (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (10 mL) and brine (8 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography (12-g silica gel cartridge, 0˜10% MeOH in CH2Cl2, major UV peak) to afford 2,2-dimethyl-3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (202 mg, 94%) as a brown oil. LC-MS Method 1 tR=1.34 min, m/z=456 (M+1); 1H NMR (CDCl3) 8.01 (d, 1H), 7.80 (s, 1H), 7.36 (dt, 6H), 7.19 (d, 2H), 6.98 (m, 3H), 5.65 (d, 1H), 2.98 (d, 1H), 2.50 (m, 2H), 2.32 (m, 1H), 2.17 (s, 2H), 1.57 (d, 3H), 1.40 (s, 3H), 1.32 (s, 3H).

Workup

  1. customThe mixture was degassed
  2. additionrefilled with N2 gas 3 times
  3. temperatureThe mixture was cooled to rt
  4. additiondiluted with EtOAc (25 mL)
  5. washwashed with water (10 mL)
  6. extractionThe aqueous layer was extracted with EtOAc (2×10 mL)
  7. washThe combined organic layers were washed with water (10 mL) and brine (8 mL)
  8. dry with materialdried over Na2SO4
  9. filtrationAfter filtration and concentration
  10. customthe residue was purified by chromatography (12-g silica gel cartridge, 0˜10% MeOH in CH2Cl2, major UV peak)

Sources & evidence

ORD record
ord-dc53089cbbdd4db2a1003b0ba172866d
Source dataset
uspto-grants-2014_06
Patent number
US08754076B2

Reaction notes

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