N-Methyl-o-phenylenediamine → HCID 86732072, compound

HRID 1486758Notes

Reaction equation

HRID 1486758 reaction equation
[CH3:1][NH:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C[Al](C)C.[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH:22]2[CH2:24][CH:23]2[C:25](OCC)=O)[CH:16]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[N:18]=[C:17]([C@@H:22]2[CH2:24][C@H:23]2[C:25]2[N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:9]=2)[CH:16]=1

Participants

5

Reactant 3

HCID 78498N-Methyl-o-phenylenediamine2×HCID 16682925TrimethylaluminumHCID 86732070HCID 86732070, compound

Product 1

HCID 86732072HCID 86732072, compound

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent3×

Procedure

To a solution of N1-methylbenzene-1,2-diamine (5.08 g, 41.5 mmol) in toluene (100 mL) was added a 2M solution of trimethylaluminum (22.85 ml, 45.7 mmol) in toluene dropwise over 2 h with periodic cooling in an ice bath to prevent an exotherm. After addition was complete, the resulting dark brown mixture was warmed to room temperature and stirred for 15 min. The mixture was re-cooled in an ice bath and a solution of 6-3 (5 g, 20.8 mmol) in toluene (20 mL) was added drop-wise over 2 h, after which the reaction was warmed to room temperature. After stirring for 18 h, the reaction was cooled in an ice bath and slowly quenched with water. The mixture was filtered through a pad of celite washing with ethyl acetate. The filtrate was repeatedly washed with saturated copper (II) sulfate solution until a yellow orange organic layer was obtained and no N1-methylbenzene-1,2-diamine was observed by LCMS. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude product which was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford racemic 6-4. The racemic compound was further purified by preparative chiral SFC on a ChiralCel OJ-H column (3 cm id×25 cm length) eluting with 70% carbon dioxide/30% methanol with 0.1% triethylamine modifier in isocratic mode at 80 mL/min. The first eluting peak was identified as the desired R,R enantiomer (6-4) and was used in subsequent steps. 1H NMR (400 MHz, CDCl3) δ 7.71-7.66 (m, 1H), 7.31-7.23 (m, 3H), 7.19 (s, 1H), 3.83 (s, 3H), 2.86-2.79 (m, 2H), 2.67 (s, 3H), 1.96 (m, 2H); MS: m/z=299.2 (M+H).

Workup

  1. temperaturewith periodic cooling in an ice bath
  2. additionAfter addition
  3. temperatureThe mixture was re-cooled in an ice bath
  4. temperatureafter which the reaction was warmed to room temperature
  5. stirringAfter stirring for 18 h
  6. temperaturethe reaction was cooled in an ice bath
  7. customslowly quenched with water
  8. filtrationThe mixture was filtered through a pad of celite
  9. washwashing with ethyl acetate
  10. washThe filtrate was repeatedly washed with saturated copper (II) sulfate solution until a yellow orange organic layer
  11. customwas obtained
  12. dry with materialThe organic layer was dried over magnesium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-dad1bc27defc47aaaa5eb987bf97ab2d
Source dataset
uspto-grants-2016_08
Patent number
US09428492B2

Reaction notes

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