Acetic Anhydride → N-(4-Hydroxy-3,5-dimethylphenyl)acetamide

HRID 1500599Notes

Reaction equation

HRID 1500599 reaction equation
[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].C1C[O:16][CH2:15][CH2:14]1.C(OC(=O)C)(=O)C>CC(O)=O.CO.CCOC(C)=O.O=[Pt]=O>[OH:12][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([NH:8][C:15](=[O:16])[CH3:14])=[CH:5][C:4]=1[CH3:11]

Participants

8

Reactant 3

HCID 7918Acetic AnhydrideHCID 8028TetrahydrofuranHCID 170302,6-Xylenol, 4-nitro-

Product 1

HCID 89896N-(4-Hydroxy-3,5-dimethylphenyl)acetamide

Reagents, catalysts & solvents 4

HCID 345198Adams' catalystCatalystHCID 176Acetic AcidSolventHCID 887MethanolSolventHCID 8857Ethyl AcetateSolvent

Procedure

A suspension of 2,6-dimethyl-4-nitrophenol (4a, 1.58 g, 9.45 mmol) in AcOH (20 ml), MeOH (15 ml), and THF (10 ml) in a hydrogenator vessel was treated with acetic anhydride (6 ml, 63.6 mmol) and PtO2 (200 mg, 0.881 mmol), pressurized to 50 p.s.i. with H2 and shaken for 24 h. The reaction mixture was returned to atmospheric pressure, diluted with EtOAc, washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b) was isolated as a white solid that was pure based upon LCMS analysis and used without further purification. Potassium carbonate (810 mg, 5.34 mmol) was added to a solution of tetrabutylammonium iodide (78.9 mg, 0.534 mmol), 3-(chloromethyl)-4-methoxybenzaldehyde (5a, 197 mg, 1.07 mmol), and N-(4-hydroxy-3,5-dimethylphenyl)acetamide (4b, 211 mg, 1.18 mmol) in 20 ml of acetonitrile. The reaction mixture was heated to 150° C. in the microwave for 1 h, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with 5-50% EtOAc/DCM gradient to afford the desired product 6a (196 mg, 56%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.28 (s, 6 H), 3.93 (s, 3 H), 4.83 (s, 2 H), 7.02 (d, J=8.4 Hz, 1H), 7.13 (s, 1 H), 7.17 (s, 2 H), 7.89 (dd, J=8.4, 2.0 Hz, 1 H), 8.12 (d, J=1.8 Hz, 1H), 9.94 (s, 1 H); LCMS: (electrospray+ve), m/z 328.2 (MH)+, tR=3.16 min, UV254=>95%. N-(4-(5-formyl-2-methoxybenzyloxy)-3,5-dimethylphenyl)acetamide (6a, 145 mg, 0.441 mmol), 2-amino-N-(furan-2-ylmethyl)benzamide (3b, 105 mg, 0.486 mmol), and 0.2 equiv of Yb(OTf)3 in 5 ml of EtOH were heated at 80° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica-gel using 7-60% ethyl acetate in hexanes to give the desired product 7a (40.9 mg, 0.078 mmol, 17.6% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 2.21 (s, 6 H), 3.77 (d, J=15.7 Hz, 1 H), 3.84 (s, 3 H), 4.41 (s, 1 H), 4.70-4.87 (m, 2 H), 5.35 (d, J=15.7 Hz, 1 H), 5.78 (s, 1 H), 6.20 (d, J=2.9 Hz, 1 H), 6.24-6.32 (m, 1 H), 6.53 (d, J=8.0 Hz, 1 H), 6.76-6.91 (m, 2 H), 7.03 (br. s., 1 H), 7.13 (s, 2 H), 7.30-7.37 (m, 2 H), 7.49 (d, J=2.0 Hz, 1 H), 7.92-8.03 (m, 1 H); LC/MS (electrospray+ve), m/z 526.2 (MH)+, Retention time t=5.71 min; Purity: UV220>98%, UV254>98%; HRMS (ESI): m/z calcd for C31H31N3O5 [M+H]+526.2351, found 526.2350.

Workup

  1. washwashed with H2O
  2. dry with materialdried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-03be179a484f4c938039c9d506563dc0
Source dataset
uspto-grants-2015_12
Patent number
US09206154B2

Reaction notes

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