Acetic Acid → 4-[3-(4-Bromo-2-methyl-phenylamino)-propyl]-tetrahydro-pyran-4-carboxylic acid methyl ester

HRID 391186Notes

Reaction equation

HRID 391186 reaction equation
[CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][O:11][C:12]([C:14]1([CH2:20][CH2:21][CH:22]=O)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].NC1C=CC=CC=1>ClCCCl.C(Cl)Cl.CO>[CH3:10][O:11][C:12]([C:14]1([CH2:20][CH2:21][CH2:22][NH:4][C:3]2[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=2[CH3:1])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]

Participants

9

Reactant 5

HCID 176Acetic AcidHCID 6115Aniline2×HCID 114234-Bromo-2-methylanilineHCID 5049666Sodium triacetoxyborohydrideHCID 584680574-(3-Oxo-propyl)tetrahydro-pyran-4-carboxylic acid methyl ester

Product 1

HCID 584680484-[3-(4-Bromo-2-methyl-phenylamino)-propyl]-tetrahydro-pyran-4-carboxylic acid methyl esterYield 46%

Reagents, catalysts & solvents 3

HCID 111,2-DichloroethaneSolvent2×HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

2-Methyl-4-bromo-aniline (930 mg, 5 mmol) was dissolved in DCE (50 mL); to this solution was transferred a solution of 4-(3-oxo-propyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (1.0 g, 5 mmol) in DCE (50 mL). The flask was submerged in a water bath at rt. To this clear solution was then added acetic acid (930 mg, 15.5 mmol, 3.1 equiv), followed by addition of powder NaBH(OAc)3 (3.18 g, 15 mmol, 3 equiv.) in 1 portion under N2 at r.t. The yellowish milky suspension was stirred at r.t. overnight. LC/MS showed m/z 372/370 at t=3.872 min. along with small amount of aniline starting material (MS: 186/188). TLC (5% of MeOH in DCM) showed no SM. of aldehyde, but aniline. The reaction was diluted with DCM (100 mL), cooled to ice-water bath, and quenched with 5 mL of conc. NH4OH (7.45M) in 150 mL of water. (2 M of NH4OH). The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The product was purified on a 25-g-silica gel column eluted with DCM to elute aniline; 2.5% MeOH in DCM for the product to get 0.85 g (46%) of the title compound as an oil.

Workup

  1. customThe flask was submerged in a water bath at rt
  2. customat t=3.872 min.
  3. temperaturecooled to ice-water bath
  4. customquenched with 5 mL of conc. NH4OH (7.45M) in 150 mL of water
  5. customThe two layers were separated
  6. extractionthe aqueous layer was extracted with DCM (20 mL×2)
  7. washThe combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL)
  8. dry with materialdried (anhydrous potassium carbonate)
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe product was purified on a 25-g-silica gel column
  12. washeluted with DCM
  13. washto elute aniline

Sources & evidence

ORD record
ord-e483030eb7e34aa09ea8cc0d31cde69a
Source dataset
uspto-grants-2013_02
Patent number
US08383814B2

Reaction notes

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