Sulfuric Acid → Acetylisatin

HRID 1598003Notes

Reaction equation

HRID 1598003 reaction equation
[C:1]([N:4]1[C:12]2C(=[CH:8][C:9](N)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])C.Cl[C:15](Cl)(Cl)[CH:16]([OH:18])O.[O-:21]S([O-])(=O)=O.[Na+].[Na+].Cl.NO.OS(O)(=O)=O>Cl.O>[C:5]([N:4]1[C:12]2[C:15](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:16](=[O:18])[C:1]1=[O:3])(=[O:21])[CH3:6]

Participants

8

Reactant 5

HCID 1118Sulfuric AcidHCID 2707Chloral HydrateHCID 24436Sodium SulfateHCID 2925071-(5-amino-2,3-dihydro-1H-indol-1-yl)ethan-1-oneHCID 443297Hydroxyamine hydrochloride

Product 1

HCID 11321AcetylisatinYield 113.5%

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 962WaterSolvent2×

Conditions

Temperature
20 °C

Procedure

A solution of 1-acetyl-5-amino-indoline (4.94 g, 28.03 mmol) in conc. HCl (250 mL) and H2O (17 mL) was added to a mixture of chloral hydrate (5.12 g, 31.0 mmol), and Na2SO4 (73.8 g, 0.52 mol) in H2O (68 mL). Once all materials were dissolved, hydroxylamine hydrochloride (6.27 g, 190 mmol) was added and the solution was heated to boiling over 30 minutes and maintained at a boil for 30 minutes. The precipitate which formed upon cooling to 20° C. was removed by filtration, washed with H2O, and dried in vacuo to constant mass to afford 6.68 g. of the 1-acetyl-5-[2-(isonitroso)acetamido]indoline (LC-MS: 248 (MH+)). This material was added in small portions over 30 minutes to conc. H2SO4 (20 mL) while stirring at 50° C. When the addition was complete the mixture was heated to 80° C. for 10 minutes, cooled to 20° C., and poured into ice/water (300 mL). The precipitate was filtered, washed with H2O and dried in vacuo to yield 6.02 g of the 1-acetyl isatin derivative (LC-MS: 248 (M+NH4+). A sample (2.68 g, 11.4 mmol) of this product was heated to 50° C. in dioxane (23 mL)/6N HCl (25 mL) for 16 hours. Concentration of the mixture in vacuo at 40° C. yielded the crude deacetyled isatin product (LC-MS: 189 (MH+)) which was redissolved in THF (50 mL) and reduced directly by addition of 1M borane/THF (114 mL, ~10 eq.). After stirring 16 hours at 20° C. the mixture was carefully quenched with H2O (50 mL), diluted with brine, and the pH adjusted to 10-11 before extraction with EtOAc. The organic extracts were pooled, dried over Na2 SO4(s), filtered and concentrated in vacuo. The residue was recrystallized from Et2O/hexanes to afford pure 1,2,3,5-tetrahydro-pyrrolo[2,3-f]indole (797 mg, LC-MS: 159 (MH+).

Workup

  1. dissolutionOnce all materials were dissolved
  2. temperaturethe solution was heated
  3. temperaturemaintained at a boil for 30 minutes
  4. customThe precipitate which formed
  5. customwas removed by filtration
  6. washwashed with H2O
  7. customdried in vacuo to constant mass
  8. customto afford 6.68 g
  9. additionWhen the addition
  10. temperaturewas heated to 80° C. for 10 minutes
  11. temperaturecooled to 20° C.
  12. filtrationThe precipitate was filtered
  13. washwashed with H2O
  14. customdried in vacuo

Sources & evidence

ORD record
ord-eb00003f80fd47fba371b138f281f192
Source dataset
uspto-grants-1998_04
Patent number
US05736534

Reaction notes

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