Ammonium Chloride → N-[2-(2-cyclopropyl-1-hydroxycyclobutyl)-phenyl]Formamide

HRID 2240478Notes

Reaction equation

HRID 2240478 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH:9]=[O:10].C[Li].C([Li])CCC.[CH:18]1([CH:21]2[CH2:24][CH2:23][C:22]2=[O:25])[CH2:20][CH2:19]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)C.C(OCC)(=O)C>[CH:18]1([CH:21]2[CH2:24][CH2:23][C:22]2([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH:9]=[O:10])[OH:25])[CH2:20][CH2:19]1

Participants

9

Reactant 5

HCID 25517Ammonium ChlorideHCID 8179142-BromoformanilideHCID 125241302-Cyclopropylcyclobutan-1-oneHCID 178418339ButyllithiumHCID 178418348HCID 178418348, compound

Product 1

HCID 86628157N-[2-(2-cyclopropyl-1-hydroxycyclobutyl)-phenyl]Formamide

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-70 °C

Procedure

In a sulfonation flask, 7.8 g (0.039 mol) N-(2-bromophenyl)formamide was dissolved in a mixture of 150 ml dry tetrahydrofuran and 150 ml dry diethyl ether. The solution was cooled to −70° C. and 25.6 ml (0.041 mol) methyllithium solution (1.6M in diethyl ether) added in 30 minutes in such a manner that the internal temperature remained constant at −70° C. Then the resulting solution was cooled to −100° C. and 25.6 ml (0.041 mol) of n-butyllithium solution (1.6M in hexane) was added in such a manner that the internal temperature remained constant at −100° C. (±2° C.). After stirring for 2 hours at −70 to −75° C., the solution was again cooled to −100° C. and 4.54 g (0.041 mol) 2-cyclopropylcyclobutan-1-one (prepared as described in Example 2) dissolved in 30 ml of dry tetrahydrofuran, was added slowly (20 minutes) at an internal temperature of −100° C. After stirring for 3 hours at −75° C., the temperature was elevated to 0° C. in ca. 30 minutes. After the addition of concentrated ammonium chloride solution, ethyl acetate was added and the organic phase was washed several times with water. After drying and evaporation of the solvent in a water jet vacuum, the crude material was obtained. Purification was achieved by flash chromatography over silica gel (eluant: hexane/ethyl acetate 1:1). Yield: 3.4 g (38% of theory) of N-[2-(2-cyclopropyl-1-hydroxycyclo-butyl)-phenyl]formamide in the form of a slightly yellow liquid.

Workup

  1. customremained constant at −70° C
  2. temperatureThen the resulting solution was cooled to −100° C.
  3. customremained constant at −100° C.
  4. custom(±2° C.)
  5. temperaturethe solution was again cooled to −100° C.
  6. additionwas added slowly (20 minutes) at an internal temperature of −100° C
  7. stirringAfter stirring for 3 hours at −75° C.
  8. waitthe temperature was elevated to 0° C. in ca. 30 minutes
  9. additionwas added
  10. washthe organic phase was washed several times with water
  11. customAfter drying
  12. customevaporation of the solvent in a water jet vacuum

Sources & evidence

ORD record
ord-05a5f6e6ecf441f39b03c1301e641747
Source dataset
uspto-grants-2010_05
Patent number
US07723371B2

Reaction notes

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