Nitric Acid → HCID 59441933, compound

HRID 1014407Notes

Reaction equation

HRID 1014407 reaction equation
FC1C=C2C(=CC=1)NC=C2.C([BH3-])#N.[Na+].C(OC(=O)C)(=O)C.[C:22]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23].[N+:35]([O-])([OH:37])=[O:36]>C(O)(=O)C.S(=O)(=O)(O)O>[C:22]([N:25]1[C:33]2[C:28](=[CH:29][C:30]([F:34])=[C:31]([N+:35]([O-:37])=[O:36])[CH:32]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]

Participants

8

Reactant 5

HCID 944Nitric AcidHCID 7918Acetic AnhydrideHCID 678615-FluoroindoleHCID 5003444Sodium cyanoborohydrideHCID 18461678HCID 18461678, compound

Product 1

HCID 59441933HCID 59441933, compound

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 1118Sulfuric AcidSolvent

Procedure

To a solution of 5-fluoro-1H-indole (5.0 g, 37 mmols) in acetic acid (300 ml) was added sodium cyanoborohydride (2.79 g, 44 mmols). After stirring overnight at rt, the reaction was concentrated under reduced pressure, redissolved in ethyl acetate (300 ml) and the pH was adjusted to 8 with saturated sodium bicarbonate. The organic layer was separated, filtered through a cotton plug, evaporated, and placed on the high vacuum for one hour prior to the next synthetic step. The crude material was then dissolved in acetic acid (100 ml), followed by the addition of acetic anhydride (3.5 ml, 37 mmols). After heating at 60 C for one hour, the reaction was poured into ice, stirred for one hour, solid was removed by vacuum filtration, rinsed with water and allowed to dry overnight under house vacuum. Next, to a solution of the 1-acetyl-5-fluoro-2,3-dihydro-1H-indole (500 mg, 2.79 mmol) in sulfuric acid (10 ml) at OC was added nitric acid (0.196 ml, 3.07 mmols) by a slow dropwise addition. After stirring 30 min at OC, the reaction was quenched by pouring into ice water. The solids were removed by vacuum filtration, redissolved in dichloromethane (50 ml), adsorbed to silica gel, and purified by LC(25% to 75% ethyl acetate/hexanes). The lower Rf spot was isolated and the structure was determined to be the desired regioisomer by IR profiling. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (s, 3 H) 3.25 (t, J=8.63 Hz, 2 H) 4.18 (t, J=8.53 Hz, 2 H) 7.50 (d, J=11.24 Hz, 1 H) 8.64 (d, J=7.22 Hz, 1 H).

Workup

  1. concentrationthe reaction was concentrated under reduced pressure
  2. dissolutionredissolved in ethyl acetate (300 ml)
  3. customThe organic layer was separated
  4. filtrationfiltered through a cotton plug
  5. customevaporated
  6. waitplaced on the high vacuum for one hour
  7. dissolutionThe crude material was then dissolved in acetic acid (100 ml)
  8. temperatureAfter heating at 60 C for one hour
  9. additionthe reaction was poured into ice
  10. stirringstirred for one hour
  11. customsolid was removed by vacuum filtration
  12. washrinsed with water
  13. customto dry overnight under house vacuum
  14. additionby a slow dropwise addition
  15. stirringAfter stirring 30 min at OC
  16. customthe reaction was quenched
  17. additionby pouring into ice water
  18. customThe solids were removed by vacuum filtration
  19. dissolutionredissolved in dichloromethane (50 ml)
  20. custompurified by LC(25% to 75% ethyl acetate/hexanes)
  21. customThe lower Rf spot was isolated

Sources & evidence

ORD record
ord-f0f3680b36f747d282e53adec378a2d5
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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