1-Naphthoic acid → 4-Methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehyde

HRID 10751

Reaction equation

HRID 10751 reaction equation
[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1.C1(C(O)=O)C2C(=CC=CC=2)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O-]C1C=CC=CC=1>C1(C)C=CC=CC=1.[OH-].[Na+].C(OCC)(=O)C>[CH3:11][O:10][C:8]1[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([O:1][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:9]=1

Participants

9

Reactant 5

HCID 68471-Naphthoic acidHCID 10796Cesium carbonate2×HCID 792052-Bromo-6-methylpyridineHCID 119047PhenolateHCID 118589982-Hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde

Product 1

HCID 219810184-Methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehydeYield 65.9%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolvent2×HCID 8857Ethyl AcetateSolvent2×HCID 14798Sodium HydroxideSolvent

Conditions

Temperature
110 °C

Procedure

Ex-122A: To a solution of 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (0.68 g, 2.9 mmol) and 2-bromo-6-methylpyridine (0.25 g, 1.4 mmol) in toluene (1.0 mL) was added ethyl acetate (0.0063 g, 0.072 mmol, 1-naphthoic acid (0.50 g, 2.9 mmol), 5 Å molecular sieves (0.36 g), cesium carbonate (0.94 g, 2.9 mmol), and copper(I) triflate-benzene complex (0.020 g, 0.036 mmol). The phenoxide crashed out of solution upon addition of cesium carbonate and additional toluene (1 mL) was added to facilitate stirring. The heterogeneous solution was immediately heated to 110° C. and aged for 24 h. Upon completion, as determined by HPLC, the reaction was diluted with a 5% sodium hydroxide solution (10 mL) and ethyl acetate (10 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (5×20 mL). The combined organic extracts were washed with a 50% brine solution (1×25 mL), brine (1×25 mL), dried over sodium sulfate and concentrated to an dark brown semi-solid. Silica gel chromatography (ethyl acetate/hexanes, 1:4) afforded 0.30 g (65%) of 4-methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehyde as a light orange solid, mp 140–141° C. 1H-NMR (300 MHz, CDCl3) δ 10.21 (s, 1H), 8.23 (s, 1H), 7.64 (dd, 1H, J=7.8, 7.2 Hz), 7.52 (d, 1H, J=3.3 Hz), 7.35 (d, 1H, J=5.1 Hz), 7.10 (dd, 1H, J=5.1, 3.3 Hz), 6.94 (d, 1H, J=7.2 Hz), 6.78 (d, 1H, J=7.8 Hz), 6.75 (s, 1H), 3.92 (s, 3H), 2.44 (s, 3H). HRMS (EI) Calcd. for C18H15NO3S: 325.0773. Found: 325.0775. Anal. Calcd. C18H15NO3S: C, 66.44; H, 4.65; N, 4.30; S, 9.85. Found: C, 60.00; H, 4.58; N, 4.05; S, 9.84.

Workup

  1. additionwas added
  2. stirringstirred for 30 min
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with ethyl acetate (5×20 mL)
  5. washThe combined organic extracts were washed with a 50% brine solution (1×25 mL), brine (1×25 mL)
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated to an dark brown semi-solid

Sources & evidence

ORD record
ord-bf7cac834a044372bd0d04983d7dc8e9
Source dataset
uspto-grants-2006_08
Patent number
US07094801B2

Linked notes

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