4-Chlorobenzoyl chloride → (2-Chloro-4-methoxyphenyl)(4-chlorophenyl)methanone

HRID 335656

Reaction equation

HRID 335656 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][C:17]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:7]

Participants

6

Reactant 4

HCID 85014-Chlorobenzoyl chlorideHCID 178333-ChloroanisoleHCID 516892Sodium BicarbonateHCID 6451240Aluminum(III) Chloride

Product 1

HCID 12585194(2-Chloro-4-methoxyphenyl)(4-chlorophenyl)methanoneYield 70.7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 4-chlorobenzoyl chloride (1.0 g, 5.8 mmol) and 1-chloro-3-methoxybenzene(823.7 mmol) in CH2Cl2 (150 mL) at 0° C. was added AlCl3 (841.5 mg, 6.4 mmol). The reaction mixture was warmed to room temperature. After 12h the reaction mixture was poured into aq. NaHCO3 and extracted with CH2Cl2 (twice). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide the crude product. Purification by silica gel chromatography provided (2-chloro-4-methoxyphenyl)(4-chlorophenyl)methanone(1.1 g, 4.1 mmol). (2-Chloro-4-methoxyphenyl)(4-chlorophenyl)methanone was dissolved in AcOH (60 mL) and 49% HBr (60 mL) was added. After 12h at 90° C. all volatiles were evaporated in vaccuo to afford (4-chlorophenyl)(2,4-dihydroxyphenyl)methanone in quantitative yield. This was dissolved in MeOH (30 mL) and THF (6 mL) and cooled to 0° C. Into the reaction mixture NaBH4 (235.5 mg, 6.2 mmol) was added. After 30 minutes the reaction was quenched with aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo. Without purification this was subjected to alkylation with 1,8-dibromoocatane (3.3 g, 12.3 mmol) and K2CO3 (1.7 g, 12.3 mmol) in DMF (45 mL). After 12h the reaction mixture was diluted with water (150 mL) and water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol). To a stirred solution of (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol) in THF (25 mL) was added N-methylprop-2-en-1-amine (746 mg, 10.5 mmol) and NaHCO3 (11.0 mmol). After 36h at room temperature the reaction mixture was filtered through a glass-filter. The filtrate was evaporated in vaccuo. Purification by silica gel chromatography provided (4-(8-(allyl(methyl)amino)octyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.5 g, 3.3 mmol); 1H-NMR (300 MHz, CDCl3); 7.29-7.17 ppm (m, 5H), 6.84 (d, J=10.1 Hz, 1H), 6.74 (s, 1H), 5.98-5.80 (m, 2H), 5.31-5.15 (m, 2H), 3.85 (t, J=7.6 Hz, 2H), 3.20-3.08 (m, 2H), 2.58-2.40 (m, 2H), 2.35 (s, 3H), 1.77-1.45 (m, 4H), 1.32-1.15 (m, 8H); 13C—NMR (75 MHz, CDCl3) 156.3 ppm, 138.3, 134.2, 131.8, 130.0, 129.6, 129.3, 116.2, 74.5, 68.8, 60.4, 43.8, 57.0, 29.6, 29.3, 28.1, 27.3, 25.9; ESI-MS calcd for C25H34Cl2NO2 [M+H]+: 450.2. found 450.2.

Workup

  1. extractionextracted with CH2Cl2 (twice)
  2. washThe combined extracts were washed with brine
  3. dry with materialdried over Na2SO4
  4. concentrationconcentrated in vaccuo
  5. customto provide the crude product
  6. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-72c0a5327cc440f596e1fa3b2eabad21
Source dataset
uspto-grants-2014_11
Patent number
US08884061B2

Linked notes

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