5-Bromo-1-indanone → tert-Butyl (R)-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 1913451Notes

Reaction equation

HRID 1913451 reaction equation
[CH2:1]1[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3][NH:2]1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C:23](=O)[CH2:22][CH2:21]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([N:2]1[CH2:3][C:4]3([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]3)[CH2:1]1)[CH2:22][CH2:21]2

Participants

6

Reactant 3

HCID 5206955-Bromo-1-indanoneHCID 5049666Sodium triacetoxyborohydrideHCID 24820512tert-Butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate

Product 1

HCID 53392276tert-Butyl (R)-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 76%

Reagents, catalysts & solvents 2

HCID 11026Titanium isopropoxideCatalystHCID 63651,1-DichloroethaneSolvent

Procedure

In a dry 1 L flask was combined tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (6.53 g, 30.9 mmol) and 5-bromoindanone (7.00 g, 30.9 mmol) in 200 mL dichloroethane. Titanium (IV) isopropoxide (18.3 mL, 61.8 mmol) was added and the reaction was stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (26.2 g, 123.6 mmol) was added and the reaction was stirred at room temperature for an additional 16 hours. The reaction was quenched with 400 mL saturated sodium bicarbonate and was stirred for 15 minutes. The mixture was passed through a thin layer of Celite®, resulting in a clear bi-phasic mixture. The two layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 17 g of a crude product as a brown oil. This material was purified via Analogix (Analogix Inc., Burlington, Wis.) chromatography eluting with 100:0→85:15 dichloromethane/methanol over 30 minutes to afford the desired product (9.82 g, 76%) as a brown foam. The enantiomers were separated via preparative chiral HPLC (Column chiralcel OJ-H, 250 mm×4.6 mm, flow-rate 2.5 ml/min, CO2/MeOH (80/20/) mobile phase with 0.1% isopropylamine) to afford the desired product (3-1a, 4.6 g, 36%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H).

Workup

  1. customIn a dry 1 L flask was combined
  2. stirringthe reaction was stirred at room temperature for an additional 16 hours
  3. customThe reaction was quenched with 400 mL saturated sodium bicarbonate
  4. stirringwas stirred for 15 minutes
  5. customresulting in a clear bi-phasic mixture
  6. customThe two layers were separated
  7. extractionthe aqueous layer was extracted twice with dichloromethane
  8. washThe combined organic layers were washed with brine
  9. dry with materialdried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto afford 17 g of a crude product as a brown oil
  13. customThis material was purified via Analogix (Analogix Inc., Burlington, Wis.) chromatography
  14. washeluting with 100:0→85:15 dichloromethane/methanol over 30 minutes

Sources & evidence

ORD record
ord-b8146286b2f14d45960097891321086e
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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