1-Chloro-4-iodobenzene → 3-(4-Chlorophenyl)-3-hydroxycyclobutane-1-carboxylic acid

HRID 1778589Notes

Reaction equation

HRID 1778589 reaction equation
[Cl-].[Li+].C([Mg]Cl)(C)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1.[O:16]=[C:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1>C1COCC1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:17]2([OH:16])[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]2)=[CH:11][CH:10]=1

Participants

5

Reactant 3

HCID 125101-Chloro-4-iodobenzeneHCID 49133583-Oxocyclobutane-1-carboxylic acidHCID 178461733HCID 178461733, compound

Product 1

HCID 755396183-(4-Chlorophenyl)-3-hydroxycyclobutane-1-carboxylic acidYield 27.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

While under argon, isopropylmagnesium chloride lithium chloride complex (1.3 M solution in THF, 160 mL, 0.208 mol) was added dropwise over 15 minutes to a solution of p-chloroiodobenzene (54.3 g, 0.227 mol) in 100 mL of dry THF at −78° C. After 1 h, 3-oxocyclobutanecarboxylic acid (7.42 g, 0.065 mol) in 40 mL of dry THF was added and the reaction mixture was allowed to warm to room temperature and stir overnight. The reaction was quenched with 1 M HCl to pH-3, and stirred 2 h. Diethyl ether was added, the solution was stirred vigorously and the phases separated. The product was leached from organic layer with 1 M NaOH, reacidified to pH-3 with 6 M HCl and extracted with diethyl ether (2×). The combined organic layers were dried over MgSO4 filtered and concentrated to give the crude product as an off-white solid. Recrystallization from diethyl ether and n-heptane afforded the subject compound as a white solid 4.03 g (27.3%). 1H NMR (DMSO-d6, 600 MHz) δ 12.25 (bs, 1H), 7.58 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 5.86 (bs, 1H), 2.74-2.80 (m, 1H), 2.62-2.65 (m, 2H), 2.53-2.57 (m, 2H). ESI MS found for C11H11ClO3 m/z [225.1/227.1 (M−1)].

Workup

  1. customThe reaction was quenched with 1 M HCl to pH-3
  2. stirringstirred 2 h
  3. additionDiethyl ether was added
  4. stirringthe solution was stirred vigorously
  5. customthe phases separated
  6. extractionextracted with diethyl ether (2×)
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give the crude product as an off-white solid
  11. customRecrystallization from diethyl ether and n-heptane

Sources & evidence

ORD record
ord-7c9e5d62d3fa4674839119560ed565a0
Source dataset
uspto-grants-2016_02
Patent number
US09266908B2

Reaction notes

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