1-Piperidinecarboxaldehyde → tert-Butyl 2-formyl-6-phenylpyridin-3-ylcarbamate

HRID 2249498Notes

Reaction equation

HRID 2249498 reaction equation
Br[C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.C([Li])CCC.[CH:27](N1CCCCC1)=[O:28]>C1COCC1>[CH:27]([C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1)=[O:28]

Participants

5

Reactant 3

HCID 174291-PiperidinecarboxaldehydeHCID 58670135tert-Butyl 2-bromo-6-phenylpyridin-3-ylcarbamateHCID 178418339Butyllithium

Product 1

HCID 58670133tert-Butyl 2-formyl-6-phenylpyridin-3-ylcarbamateYield 68.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-72 °C

Procedure

A solution of 1D (1.75 g, 5 mmol) in dry THF (50 mL) under argon was cooled to −72° C. and treated dropwise with n-butyllithium (2.5 M in hexanes, 4 mL, 10 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 hour. N-formyl piperidine (1.1 mL, 10 mmol) was added, and then the reaction was allowed to warm up to 0° C. and maintained there for an hour. The solution was quenched by the addition of 1 M aqueous HCl to bring the pH to 6-8. The reaction was stirred at RT for 5 min, extracted with EtOAc (3×50 mL). The combined organic layers 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 (0-30%) in hexane to give the title compound as a yellow solid (1.02 g, 68%). LC/MS (method A): retention time=4.24 min, (M+H-tBu)+=243. 1H NMR (CDCl3, 400 MHz): δ 10.25 (s, 1H), 10.15 (s, 1H), 8.86 (d, J=9.0 Hz, 1H), 8.00-8.02 (m, 2H), 7.87(d, J=9.0 Hz, 1H), 7.38-7.47 (m, 3H) 1.56 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 197.93, 153.16, 151.18, 138.26, 138.14, 136.51, 129.45, 129.27, 127.50, 126.78, 125.80, 82.03, 28.64.

Workup

  1. customdid not exceed −65° C
  2. additionUpon completion of the addition
  3. temperatureto warm up to 0° C.
  4. temperaturemaintained there for an hour
  5. customThe solution was quenched by the addition of 1 M aqueous HCl
  6. stirringThe reaction was stirred at RT for 5 min
  7. extractionextracted with EtOAc (3×50 mL)
  8. washThe combined organic layers were washed with saturated NaCl
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. customevaporated under reduced pressure
  12. customThe residue was purified by silica gel (110 g) column chromatography
  13. washeluting with a gradient of EtOAc (0-30%) in hexane

Sources & evidence

ORD record
ord-c10474fb807a4fb688312a550986be07
Source dataset
uspto-grants-2008_01
Patent number
US07314882B2

Reaction notes

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