Hydrochloric Acid → 3-(4-Chlorobenzyl)-3-hydroxycyclobutanecarboxylic acid

HRID 1778595Notes

Reaction equation

HRID 1778595 reaction equation
[Mg].II.[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1.[O:13]=[C:14]1[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]1.Cl>CCOCC.C1COCC1>[Cl:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:14]2([OH:13])[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15]2)=[CH:7][CH:6]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 807IodineHCID 77231-Chloro-4-(chloromethyl)benzene2×HCID 49133583-Oxocyclobutane-1-carboxylic acidHCID 5462224Magnesium2×

Product 1

HCID 816983983-(4-Chlorobenzyl)-3-hydroxycyclobutanecarboxylic acidYield 59.3%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent3×HCID 8028TetrahydrofuranSolvent

Procedure

In a dry flask, under argon, magnesium (1.7 g, 70.11 mmol), a crystal of I2 and just enough Et2O to cover the magnesium was heated to reflux until the purple color dissipated (ca. 10 min.). Approximately 10% of a solution of 4-chlorobenzyl chloride (11.3 g, 70.11 mmol) in Et2O (20 mL) was added all at once and reflux was continued until the solution became brown. While maintaining a gentle reflux, the remainder of the 4-chlorobenzyl chloride solution was slowly added. After the addition was complete, heating was continued for 0.5 h. The solution was cooled to room temperature and added to a solution of 3-oxocyclobutanecarboxylic acid (2 g, 17.53 mmol) in THF (30 mL) pre-cooled to 0° C. Once the addition was complete, the resulting solution was allowed to warm to room temperature with continued stirring for 16 h. The reaction mixture was then poured into a solution of ether and 1 M HCl. The layers were separated and the aqueous phase was extracted with ether (3×). The combined extracts were concentrated, dissolved in 1 M NaOH and washed with ether. The aqueous phase was re-acidified with 2 M HCl and extracted with Et2O, dried over MgSO4 and concentrated to give the subject compound as a white solid (2.5 g, 59%) of white solid. 1H NMR (CDCl3, 500 MHz) δ 7.44 (d, J=8.24 Hz, 2H), 7.35 (d, J=8.24 Hz, 2H), 3.02 (s, 2H), 2.90-2.84 (m, 1H), 2.66-2.62 (m, 2H), 2.47-2.42 (m, 2H). ESI MS found for C12H13ClO3 m/z [239.1 (M−1)].

Workup

  1. temperatureto reflux until the purple color
  2. custom(ca. 10 min.)
  3. temperaturereflux
  4. temperatureWhile maintaining a gentle reflux
  5. additionAfter the addition
  6. temperatureheating
  7. temperaturepre-cooled to 0° C
  8. additionOnce the addition
  9. temperatureto warm to room temperature
  10. customThe layers were separated
  11. extractionthe aqueous phase was extracted with ether (3×)
  12. concentrationThe combined extracts were concentrated
  13. dissolutiondissolved in 1 M NaOH
  14. washwashed with ether
  15. extractionextracted with Et2O
  16. dry with materialdried over MgSO4
  17. concentrationconcentrated

Sources & evidence

ORD record
ord-5ed3884b66724f03847de5a51a610d9c
Source dataset
uspto-grants-2016_02
Patent number
US09266908B2

Reaction notes

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