N,N,N',N'-Tetramethylethylenediamine → tert-Butyl 4-formyl-6-phenylpyridin-3-ylcarbamate

HRID 2221094Notes

Reaction equation

HRID 2221094 reaction equation
[C:1]1([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.C([Li])CCC.[CH:34](N1CCCCC1)=[O:35]>C1COCC1>[CH:34]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=[CH:11][C:10]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:35]

Participants

6

Reactant 4

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 174291-PiperidinecarboxaldehydeHCID 50999077tert-Butyl (6-phenylpyridin-3-yl)carbamateHCID 178418339Butyllithium

Product 1

HCID 58671548tert-Butyl 4-formyl-6-phenylpyridin-3-ylcarbamateYield 44%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-72 °C

Procedure

A solution of 3B (3.3 g, 12.21 mmol) in dry THF (50 mL) and TMEDA (4.6 mL, 30.53 mmol) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 12.2 mL, 30.53 mmol) at such a rate so that the temperature did not exceed −65° C. Upon completion of the addition, the reaction was stirred at −72° C. for an additional 15 min and then at −20° C. for 1.5 h. The reaction was cooled again to −72° C., and N-formyl piperidine (2.7 mL, 24.4 mmol) was added while the temperature was maintained below −65° C. The mixture was allowed to stir at RT for 30 min. After this time, no starting material was detected by LC-MS. The solution was cooled to 0° C. and quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 15 min, extracted with EtOAc (3×100 mL). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by silica gel (110 g) column chromatography, eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a yellow solid (1.6 g, 44%). LC/MS (method A): retention time=2.79 min, (M+MeOH+H)+=331.

Workup

  1. customdid not exceed −65° C
  2. additionUpon completion of the addition
  3. waitat −20° C. for 1.5 h
  4. temperatureThe reaction was cooled again to −72° C.
  5. temperaturewas maintained below −65° C
  6. stirringto stir at RT for 30 min
  7. temperatureThe solution was cooled to 0° C.
  8. customquenched by the addition of 1 M aqueous HCl
  9. stirringThe reaction was stirred at RT for 15 min
  10. extractionextracted with EtOAc (3×100 mL)
  11. washThe combined organics were washed with saturated NaCl
  12. dry with materialdried over Na2SO4
  13. filtrationfiltered
  14. customevaporated under reduced pressure
  15. customThe residue was purified by silica gel (110 g) column chromatography
  16. washeluting with a gradient of EtOAc (0-60%) in hexane

Sources & evidence

ORD record
ord-9fc7eabf9fac432682c5c62448c89239
Source dataset
uspto-grants-2008_05
Patent number
US07368458B2

Reaction notes

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