Ammonium Chloride → tert-butyl benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate

HRID 1969867Notes

Reaction equation

HRID 1969867 reaction equation
[Cl:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.[Li]CCCC.[CH2:27]([N:34]([C:42]12[CH2:49][CH2:48][C:45]([CH:50]=[O:51])([CH2:46][CH2:47]1)[CH2:44][CH2:43]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:27]([N:34]([C:42]12[CH2:47][CH2:46][C:45]([CH:50]([C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]4[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:4]=34)[OH:51])([CH2:44][CH2:43]1)[CH2:48][CH2:49]2)[C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 467363645-Chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridineHCID 58557601Tert-butyl benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamateHCID 178418339Butyllithium

Product 1

HCID 58557653tert-butyl benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamateYield 64%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1.33 g, 3.06 mmol, Adesis) in THF (25 mL) at about −78° C. was added n-BuLi (1.6 M solution in hexanes, 2.00 mL, 3.20 mmol) at such a rate that the internal temperature did not exceed about −70° C. The reaction mixture was stirred for about 45 min and a solution of tert-butyl benzyl(4-formylbicyclo[2.2.2]octan-1-yl)carbamate (1.05 g, 3.06 mmol) in THF (6 mL) was added dropwise. The reaction mixture was stirred at about −78° C. for about 1 h and was slowly warmed to ambient temperature and stirred for about 1 h. Saturated aqueous NH4Cl and EtOAc (10 mL each) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×10 mL) and the combined organics were washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The remaining oil was purified by silica gel chromatography eluting with a gradient of 0-40% EtOAc in heptane to give tert-butyl benzyl(4-((5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)(hydroxy)methyl)bicyclo[2.2.2]octan-1-yl)carbamate (1.27 g, 64%) as a clear colorless oil: LC/MS (Table 1, Method o) Rt=3.78 min; MS m/z: 652 (M+H)+.

Workup

  1. customdid not exceed about −70° C
  2. stirringThe reaction mixture was stirred at about −78° C. for about 1 h
  3. stirringstirred for about 1 h
  4. customthe layers were separated
  5. extractionThe aqueous phase was extracted with EtOAc (2×10 mL)
  6. washthe combined organics were washed with brine (10 mL)
  7. dry with materialdried over anhydrous MgSO4
  8. filtrationfiltered
  9. customThe remaining oil was purified by silica gel chromatography
  10. washeluting with a gradient of 0-40% EtOAc in heptane

Sources & evidence

ORD record
ord-e67add690b264a4883009aea6b4b91d1
Source dataset
uspto-grants-2013_04
Patent number
US08426411B2

Reaction notes

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