1-(4-Bromobenzyl)pyrrolidine → 3-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanol

HRID 1241516Notes

Reaction equation

HRID 1241516 reaction equation
Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(O)(C)C.C(=O)=O.C([Li])CCC.[N:26]1([CH2:32][CH:33]2[CH2:36][C:35](=[O:37])[CH2:34]2)[CH2:31][CH2:30][CH2:29][CH2:28]C1>C1COCC1>[N:26]1([CH2:32][CH:33]2[CH2:36][C:35]([C:2]3[CH:13]=[CH:12][C:5]([CH2:6][N:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=3)([OH:37])[CH2:34]2)[CH2:28][CH2:29][CH2:30][CH2:31]1

Participants

6

Reactant 4

HCID 127380041-(4-Bromobenzyl)pyrrolidineHCID 219349183-Piperidin-1-ylmethyl-cyclobutanone2×HCID 86586944Isopropanol carbon dioxideHCID 178418339Butyllithium

Product 1

HCID 219348323-Pyrrolidin-1-ylmethyl-1-(4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanolYield 58%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a stirring solution of 1-(4-Bromo-benzyl)-pyrrolidine (Lednicer, Daniel; Lyster, Stanley C.; Duncan, Gordon W. Mammalian antifertility agents. IV. Basic 3,4-dihydronaphthalenes and 1,2,3,4-tetrahydro-1-naphthols. Journal of Medicinal Chemistry (1967), 10(1), 78–84, J. Org. Chem; EN; 46; 17; 1981; 3571–3574) (0.71 g, 2.96 mmol) in THF (13 mL) at −78° C. (isopropanol/CO2) was added a solution of n-butyl lithium (1.6 mL, 3.93 mmol, 2.5 M hexanes). After 15 minutes a pre-cooled (−78 □C) solution of 3-pyrrolidin-1-ylmethyl-cyclobutanone (Intermediate 6, General procedure B Step C) (0.2 g, 1.3 mmol, in 3 mL THF) was added down the side of the flask. After TLC analysis indicated complete consumption of starting material the reaction was quenched cold by the addition of a saturated solution of NH4Cl. The reaction was then warmed to room temperature and diluted with CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were discarded. The aqueous layer was then extracted with 3:1 (CHCl3:isopropyl alcohol) and the combined organic layers were dried over magnesium sulfate, filtered through a fritted funnel, and concentrated under reduced pressure. The material was purified by trituration using ether:hexanes to yield the title compound (0.24 mg, 58% yield) as a colorless solid and a mixture of cis:trans isomers.

Workup

  1. additionwas added down the side of the flask
  2. customconsumption of starting material the reaction
  3. customwas quenched cold by the addition of a saturated solution of NH4Cl
  4. additiondiluted with CH2Cl2
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with CH2Cl2
  7. extractionThe aqueous layer was then extracted with 3:1 (CHCl3:isopropyl alcohol)
  8. dry with materialthe combined organic layers were dried over magnesium sulfate
  9. filtrationfiltered through a fritted funnel
  10. concentrationconcentrated under reduced pressure
  11. customThe material was purified by trituration

Sources & evidence

ORD record
ord-15436cac55334815806e01724a9ab254
Source dataset
uspto-grants-2006_10
Patent number
US07115600B2

Reaction notes

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