4-Bromo-2-chloroanisole → 1-(3-Bromophenyl)-1-(3-chloro-4-methoxyphenyl)-4-fluoro-1H-isoindol-3-amine

HRID 1662195Notes

Reaction equation

HRID 1662195 reaction equation
C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19](/[C:23](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]\S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>O1CCCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1

Participants

6

Reactant 4

HCID 30165374-Bromo-2-chloroanisoleHCID 21893726Hydrochloride methanolHCID 58579486HCID 58579486, compoundHCID 178418306HCID 178418306, compound

Product 1

HCID 585795311-(3-Bromophenyl)-1-(3-chloro-4-methoxyphenyl)-4-fluoro-1H-isoindol-3-amineYield 42%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

To tetrahydrofuran (20 mL) at −100° C. was added tert-butyllithium (1.7M in pentane, 4.30 mL, 7.31 mmol) dropwise over 5 min. 4-Bromo-2-chloro-1-methoxybenzene (0.81 g, 3.66 mmol) dissolved in tetrahydrofuran (5 mL) was added over 10 min. The mixture was stirred for 5 min then was (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.241 g, 3.05 mmol) in tetrahydrofuran (10 mL) added over 10 min. The reaction mixture was held at −100° C. for 20 min and then slowly allowed to reach r.t. over night. Hydrogen chloride-methanol solution (14.63 mL, 18.29 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to give the title compound (570 mg, 42%). MS (ES+) m/z 445, 447 [M+1]+.

Workup

  1. additionwas added over 10 min
  2. additionadded over 10 min
  3. waitThe reaction mixture was held at −100° C. for 20 min
  4. waitto reach r.t. over night
  5. stirringthe resulting mixture was stirred at r.t. for 1 h
  6. concentrationThe mixture was concentrated
  7. custompurified on a silica gel column
  8. washeluted with 0-10% 0.1M NH3 in MeOH in DCM

Sources & evidence

ORD record
ord-2a1791d7919b4fc6ab8cb20f042957eb
Source dataset
uspto-grants-2011_10
Patent number
US08030500B2

Reaction notes

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