5-Bromosalicylaldehyde → tert-Butyl 4-(3-formyl-4-hydroxyphenyl)piperazine-1-carboxylate

HRID 2036051Notes

Reaction equation

HRID 2036051 reaction equation
C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].C(O)(=O)C.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:15]2[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=2)[CH:20]=[O:21])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]

Participants

10

Reactant 4

HCID 728635-BromosalicylaldehydeHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 143452tert-Butyl piperazine-1-carboxylateHCID 23676156Sodium t-butoxide

Product 1

HCID 23508726tert-Butyl 4-(3-formyl-4-hydroxyphenyl)piperazine-1-carboxylateYield 0.6%

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 167845palladium(II) acetateCatalystHCID 176Acetic AcidSolventHCID 962WaterSolventHCID 1140TolueneSolvent2×

Conditions

Temperature
42 °C

Procedure

Toluene (9.7 L) was introduced into a reactor and degassed using vacuum/nitrogen. Under nitrogen at 23° C. was palladium acetate (11.0 g, 0.049 mol, 0.01 equiv.) was loaded and the mixture was stirred until complete dissolution of palladium. A solution of tri-tert-butyl-phosphine (10.0 g, 0.049 mol, 0.01 equiv.) in toluene (0.3 L) was then added, followed by the addition of 5-bromo-2-hydroxybenzaldehyde (1000 g, 4.97 mol, 1 equiv.), tert-butyl-1-piperazine-carboxylate (1065.4 g, 5.72 mol, 1.1 equiv.) and sodium-tert-butoxide (1052.4 g, 10.9 mol, 2.2 equiv.). The resulting yellow-orange solution was stirred for 22 h at 42° C. The red-brownish slurry was mixed with a mixture (pH around 5-6) of distilled water (8 L) and glacial acetic acid (800 mL), and stirred for 10 min. The organic phase was separated from the aqueous phase and washed twice with distilled water (2×8 L). The organic phase was then dried by addition of sodium sulphate (2.5 kg), stirred for 30 min. and filtered. The resulting dark-orange organic phase was weighed (9.65 kg) and an aliquot (100 g) was taken. The aliquot was concentrated in vacuo to yield a dark-orange oil which was purified by column chromatography (SiO2, h: 30 cm, d: 4 cm, eluant: MTBE/heptane 1:1). The named compound was obtained as yellow crystals (8.9 g). Calculation of the total yield from the aliquot gave 56%. MS (ES+): 307 (M+H).

Workup

  1. customdegassed
  2. customat 23° C.
  3. stirringstirred for 10 min
  4. customThe organic phase was separated from the aqueous phase
  5. washwashed twice with distilled water (2×8 L)
  6. dry with materialThe organic phase was then dried by addition of sodium sulphate (2.5 kg)
  7. stirringstirred for 30 min.
  8. filtrationfiltered
  9. concentrationThe aliquot was concentrated in vacuo
  10. customto yield a dark-orange oil which
  11. customwas purified by column chromatography (SiO2, h: 30 cm, d: 4 cm, eluant: MTBE/heptane 1:1)

Sources & evidence

ORD record
ord-2db8430ebf134ea4810d970a73d55b01
Source dataset
uspto-grants-2013_11
Patent number
US08575161B2

Reaction notes

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