Pyridine → (+/-)-4-(alpha-(2,5-dimethyl-4-pyridyl)-alpha,3-dihydroxybenzyl)-N,N-diethylbenzamide

HRID 1460109Notes

Reaction equation

HRID 1460109 reaction equation
Br[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([CH3:9])[CH:3]=1.C([Li])CCC.[Si]([O:22][C:23]1[CH:24]=[C:25]([CH:41]=[CH:42][CH:43]=1)[C:26]([C:28]1[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1)=[O:27])(C(C)(C)C)(C)C.N1C=CC=CC=1>C(OCC)C>[CH3:9][C:4]1[CH:3]=[C:2]([C:26]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[O:33])=[CH:30][CH:29]=2)([OH:27])[C:25]2[CH:41]=[CH:42][CH:43]=[C:23]([OH:22])[CH:24]=2)[C:7]([CH3:8])=[CH:6][N:5]=1

Participants

6

Reactant 4

HCID 1049PyridineHCID 223175304-Bromo-2,5-dimethylpyridineHCID 545736974-(3-((tert-butyldimethylsilyl)oxy)benzoyl)-N,N-diethylbenzamideHCID 178418339Butyllithium

Product 1

HCID 54313109(+/-)-4-(alpha-(2,5-dimethyl-4-pyridyl)-alpha,3-dihydroxybenzyl)-N,N-diethylbenzamideYield 48.8%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent2×

Conditions

Temperature
-78 °C

Procedure

A portion of the 4-bromo-2,5-dimethylpyridine (15.4 g, 83.0 mmol) was dissolved in 500 mL of anhydrous diethyl ether and chilled to -78° C. n-Butyllithium (52 mL, 1.6M in hexanes) was added dropwise and the resulting slurry was stirred for 30 minutes. 4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)-N,N-diethylbenzamide (34.2 g, 83.0 mmol) was dissolved in 250 mL of anhydrous diethyl ether and chilled to -78° C. The lithiated pyridine was slowly transferred via cannula to the diarylketone solution. The temperature was allowed to rise to -40° C. for 4.5 hours. The reaction was quenched with saturated aqueous ammonium chloride. The diethyl ether layer was separated, the solvent was removed, and the residue was redissolved in 300 mL acetonitrile. Tetraethylammonium fluoride hydrate (19.8 g) was added, and the reaction was stirred overnight. The solvent was removed, and the residue was redissolved in 500 mL 1M hydrochloric acid and washed with 500 mL of diethyl ether. The pH of the aqueous solution was adjusted to 8 and the solution was extracted with dichloromethane. The solvent was removed and the residue was crystallized from acetonitrile to give 16.4 g (48%) of (±)-4-(α-(2,5-dimethyl-4-pyridyl)-α,3-dihydroxybenzyl)-N,N-diethylbenzamide.

Workup

  1. additionwas added dropwise
  2. waitto rise to -40° C. for 4.5 hours
  3. customThe reaction was quenched with saturated aqueous ammonium chloride
  4. customThe diethyl ether layer was separated
  5. customthe solvent was removed
  6. dissolutionthe residue was redissolved in 300 mL acetonitrile
  7. additionTetraethylammonium fluoride hydrate (19.8 g) was added
  8. stirringthe reaction was stirred overnight
  9. customThe solvent was removed
  10. dissolutionthe residue was redissolved in 500 mL 1M hydrochloric acid
  11. washwashed with 500 mL of diethyl ether
  12. extractionthe solution was extracted with dichloromethane
  13. customThe solvent was removed
  14. customthe residue was crystallized from acetonitrile

Sources & evidence

ORD record
ord-d5431de9fd4f40039160f10120d91d80
Source dataset
uspto-grants-1998_12
Patent number
US05854249

Reaction notes

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