Lithium Chloride → tert-butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

HRID 643554Notes

Reaction equation

HRID 643554 reaction equation
[F:1][C:2]1[CH:11]=[CH:10][C:9](I)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Li+].[Cl-].C[Sn](C)(C)[C:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.[Cl-].[Na+].O.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]>[F:1][C:2]1[CH:11]=[CH:10][C:9]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]

Participants

9

Reactant 5

HCID 433294Lithium ChlorideHCID 516892Sodium BicarbonateHCID 521585Tris(furan-2-yl)phosphaneHCID 220229891-t-Butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridineHCID 24820379Methyl 2-fluoro-5-iodobenzoate

Product 1

HCID 57880514tert-butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
90 °C

Procedure

Methyl 2-fluoro-5-iodobenzoate (5.01 g, 17.9 mmol) was combined with LiCl (1.52 g, 35.7 mmol) and tert-butyl 4-(trimethylstannyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.28 g, 12.3 mmol) in 100 mL of DMF. After stirring for 20 min under a nitrogen atmosphere, Pd2dba3 (218 mg, 0.238 mmol) and P(2-furyl)3 (276 mg, 1.19 mmol) were added and the reaction mixture was warmed to 90° C. under a nitrogen atmosphere and stirred for 1 h 45 min. The reaction mixture was then stirred at rt overnight. Then the reaction temperature was brought again to 90° C. for 1 h. To the mixture was added saturated NaHCO3 solution and brine. The resulting aqueous mixture was then extracted three times with ether. The ethereal layers were combined and washed four times with water, dried over anhydrous MgSO4, filtered, and concentrated. Purification by MPLC (silica, 5-25% gradient of ethyl actetate/hexanes, over 2L volume) gave tert-butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate. 1H NMR (500 MHz, CDCl3) δ 7.94 (dd, J=7.0, 2.5 Hz, 1H), 7.53 (m, 1H), 7.13 (dd, J=10, 8.5 Hz, 1H), 6.07 (br s, 1H), 4.10 (br s, 2H), 3.96 (s, 3H), 3.66 (t, 6 Hz, 2H), 2.53 (br m, 2H), 1.52 (s, 9H). ESI-MS calc. for C18H22FNO4: 335; Found: 236 (M+Boc+H).

Workup

  1. stirringstirred for 1 h 45 min
  2. stirringThe reaction mixture was then stirred at rt overnight
  3. waitThen the reaction temperature was brought again to 90° C. for 1 h
  4. extractionThe resulting aqueous mixture was then extracted three times with ether
  5. washwashed four times with water
  6. dry with materialdried over anhydrous MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by MPLC (silica, 5-25% gradient of ethyl actetate/hexanes, over 2L volume)

Sources & evidence

ORD record
ord-ad2e6d550f8f4e80b2da191386143494
Source dataset
uspto-grants-2010_04
Patent number
US07700591B2

Reaction notes

Loading…