3-Bromobenzaldehyde → 3-[4-(1-Piperidinyl)-1-butyn-1-yl]benzaldehyde

HRID 268621Notes

Reaction equation

HRID 268621 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:11][C:12]#[CH:13]>[Cu]I.N1CCCC1>[N:14]1([CH2:10][CH2:11][C:12]#[C:13][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1

Participants

5

Reactant 2

HCID 765833-BromobenzaldehydeHCID 131559861-(But-3-yn-1-yl)piperidine

Product 1

HCID 224934833-[4-(1-Piperidinyl)-1-butyn-1-yl]benzaldehydeYield 86%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 31268PyrrolidineSolvent2×

Conditions

Temperature
50 °C

Procedure

To the mixture of Pd(PPh3)Cl2 (24 mg, 0.034 mmol, 0.02 equiv.), CuI (13 mg, 0.068 mmol, 0.04 equiv.) and 3-bromobenzaldehyde (0.316 g, 1.7 mmol, 1 equiv.), pyrrolidine (10 mL) were added under N2. The use of pyrrolidine is preferred in the context of this synthesis. A stream of N2 was bubbled into to the solution for 5 min, and then 1-but-3-ynyl-piperidine (0.46 g, 3.3 mmol, 2 equiv.) was added. The reaction mixture was stirred at 50° C. for 40 h. This temperature is preferred in the context of this synthesis. On TLC and HPLC, the reaction was complete. The white precipitate (Et3N.HBr) was filtered and washed with EtOAc. The solvent was evaporated and the residue was re-dissolved in EtOAc. The organic layer was washed with aqueous NaOH (1N) twice, and dried over MgSO4. After filtration, the EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes) and washed with EtOAc. The solvent was evaporated to afford the product as a brown oil (0.35 g, 1.45 mmol, 86%); purity >95% on HPLC; MS M+H+242. This product does not need further purification in its use for subsequent steps in the context of this invention. A yield of 86% is in marked contrast with conventional methodologies, which produce the title compound with typical yields that do not exceed 30%.

Workup

  1. additionwere added under N2
  2. customA stream of N2 was bubbled into to the solution for 5 min
  3. customThis temperature is preferred in the context of this synthesis
  4. filtrationThe white precipitate (Et3N.HBr) was filtered
  5. washwashed with EtOAc
  6. customThe solvent was evaporated
  7. dissolutionthe residue was re-dissolved in EtOAc
  8. washThe organic layer was washed with aqueous NaOH (1N) twice
  9. dry with materialdried over MgSO4
  10. filtrationAfter filtration
  11. additionthe EtOAc solution was poured directly onto a short pad of silica gel (neutralized with 5% Et3N in hexanes)
  12. washwashed with EtOAc
  13. customThe solvent was evaporated

Sources & evidence

ORD record
ord-c2362e1ae15d422ebd66635195076574
Source dataset
uspto-grants-2008_11
Patent number
US07446104B2

Reaction notes

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