Sulfuric Acid → 3-(4-Chlorobenzyl)-3-formamidocyclobutanecarboxylic acid
Reaction equation
[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2(O)[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[C-]#[N:18].[K+].OS(O)(=O)=O.[C:25]([OH:31])(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2([NH:18][CH:25]=[O:31])[CH2:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1Participants
Conditions
- Temperature
- 0 °C
Procedure
A solution of 3-(4-chlorobenzyl)-3-hydroxycyclobutanecarboxylic acid (1 g, 4.17 mmol) in TFA (17.5 mL) was charged with KCN (813 mg, 12.5 mmol), cooled to 0° C. and treated with H2SO4 (3.5 mL) dropwise. The cooling bath was removed and stirring was continued for 1.5 h. Once the reaction was complete, the mixture was re-cooled to 0° C. diluted with water, and extracted with diethyl ether. The organic layer was washed successively with 1M NaOH and saturated aqueous sodium chloride. The solution was dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (gradient 1-20% methanol in dichloromethane) afforded the subject compound (500 mg, 45% yield). 1H NMR (DMSO-d6, 600 MHz) δ 12.15 (bs, 1H), 8.38 (s, 1H), 7.88 (d, J=1.13 Hz, 1H), 7.36-7.32 (m, 4H), 2.94-2.89 (m, 1H), 2.57-2.53 (m, 1H), 2.36-2.32 (m, 1H), 2.26-2.22 (m, 1H), 2.03-1.96 (m, 1H), 1.95-1.88 (m, 2H). ESI MS found for C13H14ClNO3 m/z [266.1 (M−1)].
Workup
- customThe cooling bath was removed
- temperaturethe mixture was re-cooled to 0° C.
- additiondiluted with water
- extractionextracted with diethyl ether
- washThe organic layer was washed successively with 1M NaOH and saturated aqueous sodium chloride
- dry with materialThe solution was dried over MgSO4
- filtrationfiltered
- concentrationconcentrated
- customPurification by flash column chromatography (gradient 1-20% methanol in dichloromethane)
Sources & evidence
- ORD record
- ord-18be15a21d7f4e07adde8fbaa26048fc
- Source dataset
- uspto-grants-2016_02
- Patent number
- US09266908B2
Reaction notes
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