Toluene → (S)-2-methyl-4-(6-morpholino-5-nitropyridin-3-yl)morpholine

HRID 1431388Notes

Reaction equation

HRID 1431388 reaction equation
Cl[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:17][CH:18]1[O:23][CH2:22][CH2:21][NH:20][CH2:19]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC([O-])(C)C.[Na+].C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][C@@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=2)[CH2:19]1.[CH3:17][C@H:18]1[O:23][CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=2)[CH2:19]1

Participants

8

Reactant 5

HCID 1140TolueneHCID 4106152-MethylmorpholineHCID 23676156Sodium t-butoxideHCID 596312064-(5-Chloro-3-nitropyridin-2-yl)morpholineHCID 672859322-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl

Product 2

HCID 59631130(S)-2-methyl-4-(6-morpholino-5-nitropyridin-3-yl)morpholineHCID 59631580(R)-2-methyl-4-(6-morpholino-5-nitropyridin-3-yl)morpholine

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Procedure

A solution of 4-(5-chloro-3-nitropyridin-2-yl)morpholine (2 g, 8.21 mmol; described herein), 2-methylmorpholine (996 mg, 9.85 mmol), tris(dibenzylideneacetone)dipalladium(0) (526 mg, 0.58 mmol), 2-(dicyclohexylphosphino)-2,4,6,-tri-i-propyl-1,1-biphenyl (587 mg, 1.23 mmol), sodium 2-methylpropan-2-olate (1.6 g, 16.4 mmol), and toluene (126 mL, 119 mmol) was refluxed overnight then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with satd aq. sodium bicarbonate and brine, and the organic layer dried (magnesium sulfate) and concentrated. Column chromatography and chiral separation afforded (S)-2-methyl-4-(6-morpholino-5-nitropyridin-3-yl)morpholine and (R)-2-methyl-4-(6-morpholino-5-nitropyridin-3-yl)morpholine as red solids (absolute configuration not determined and assigned randomly). Mass Spectrum (ESI) m/e=309.2 (M+1).

Workup

  1. temperaturewas refluxed overnight
  2. concentrationconcentrated
  3. washwashed with satd aq. sodium bicarbonate and brine
  4. dry with materialthe organic layer dried (magnesium sulfate)
  5. concentrationconcentrated
  6. customColumn chromatography and chiral separation

Sources & evidence

ORD record
ord-838e148494d5423f829681dbd6648e16
Source dataset
uspto-grants-2015_01
Patent number
US08940724B2

Reaction notes

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