Morpholine → 4-(5-Bromopyridin-3-yl)morpholine

HRID 712677

Reaction equation

HRID 712677 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.CC([O-])(C)C.[Na+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>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]>[Br:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=[N:4][CH:5]=1

Participants

7

Reactant 4

HCID 8083MorpholineHCID 693693,5-DibromopyridineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxide

Product 1

HCID 467396144-(5-Bromopyridin-3-yl)morpholineYield 50.8%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

In a sealable tube, to a mixture of 3,5-dibromo-pyridine (3.3 g, 13.8 mmol) and NaOtBu (0.051 g, 23 mmol) in toluene (70 mL), is added morpholine (1.0 g, 11.5 mmol). The mixture is bubbled with Argon for 5 min, and then BINAP (428.9 mg, 0.69 mmol) and Pd2(dba)3 (210.2 mg, 0.23 mmol) are added. The reaction mixture is bubbled with Argon for another 5 min. Then the cap is sealed and the reaction mixture is heated at 120° C. overnight and then is cooled to room temperature. The reaction mixture is filtered through diatomaceous earth and washed with DCM. The filtrate is partitioned between water and DCM. The aqueous phase is further extracted with DCM (2×). The combined DCM phases are concentrated. The crude is purified by flash chromatography on a silica gel column (EtOAc/heptane 0 to 50% gradient, then 50%) to provide 1.42 g of 4-(5-bromo-3-pyridyl)morpholine.

Workup

  1. customThe mixture is bubbled with Argon for 5 min
  2. customThe reaction mixture is bubbled with Argon for another 5 min
  3. customThen the cap is sealed
  4. temperatureis cooled to room temperature
  5. filtrationThe reaction mixture is filtered through diatomaceous earth
  6. washwashed with DCM
  7. customThe filtrate is partitioned between water and DCM
  8. extractionThe aqueous phase is further extracted with DCM (2×)
  9. concentrationThe combined DCM phases are concentrated
  10. customThe crude is purified by flash chromatography on a silica gel column (EtOAc/heptane 0 to 50% gradient

Sources & evidence

ORD record
ord-7a234e61718c4a5fb21caffcce39713f
Source dataset
uspto-grants-2015_11
Patent number
US09181272B2

Linked notes

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