Cinchonanium, 9-hydroxy-1-(phenylmethyl)-, chloride, (9S)-

Solid

Racemic biaryl 7 (93mg, 0.26mmol) was placed in a 50mL flask and acetone (2mL) was added, followed by The outer wall of the 250 ml one-necked flask was wrapped in tin box paper, protected from light, 10percent (34 mmol) of cinchonidine, 4.4 ml (38 mmmol) of benzyl chloride, and 100 ml of toluene were added, and refluxed for 2 h. After completion of the reaction, the mixture was cooled to room temperature, suction filtered, and the filter cake was washed twice with diethyl ether and dried to give quantitative yield (8S, 9R)-(-)-N-benzyl chloride cinchonidineGeneral procedure: The alkaloid (12.3 mmol, 1 eq.) and the appropriate substituted benzylic halide derivative(12.3 mmol, 1 eq.) were dissolved in THF (40 mL) with addition of a trace of NaI. The mixture washeated to reflux overnight and then cooled and stirred at ambient temperature for 1 h. In most cases theproduct precipitated as an off-white solid, but where this was not the case and the mixture containedonly a small amount of solid or no solid at all, then diethyl ether (20 mL) was added dropwise.The solid was removed via filtration and washed with THF (50 mL) or ether:THF, (1:1, v/v, 50 mL)and was dried under reduced pressure at 40 °C. Where the solid formed was not a fine powder it was then taken up in DCM and this solution was then added dropwise to rapidly stirring ether (100 mL).This usually gives a finely divided solid that could be filtered and dried. (Note: The cinchonine derivedPTCs are usually very insoluble. The quinidine derived PTCs are often completely soluble at the endof the reaction.) The di(t-butyl)benzyl PTC was prepared according to the standard procedure aboveand was filtered directly from the reaction mixture.General procedure: (Part 1) To a stirred solution of Cinchona alkaloid (either Quinine, Quinidine, Cinchonine or Cinchonidine) (1 equiv.) in THF (0.1 M) was added the required arylmethyl halide compound (1.2 equiv.) at room temperature. The reaction mixture was refluxed overnight, cooled to room temperature and all volatiles were removed invacuo. The residue was then dissolved in CH2Cl2 (typically 2 mL for 1 mmol of starting material) and the resulting solution was added dropwise onto Et2O (typically 30 mL for 1 mmol of starting material) with vigorous stirring. The resulting precipitate was then filtered, washed thoroughly with Et2O, and further dried under high vacuum for 2 hours, yielding the intermediate alcohol product in an excellent yield. (Part2) This product (1 equiv.) was dissolved in CH2Cl2 (0.2 M). Methyl iodide (3 equiv.) and an aqueous sodium hydroxide solution (50 percentw, 5 equiv.) were successively added at room temperature. The reaction mixturewas stirred at room temperature for 4 h, before water (typically 20 mL for 1 mmol of starting material) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo (N.B: washing with brine is prohibited to avoid the I/Cl anion exchange). Purification by column chromatography on silica gel, eluting with MeOH/Acetone/CH2Cl2 (0:10:90 to 10:10:90), afforded the desired Cinchona alkaloid quaternary ammonium salt in a moderate to excellent yield.General procedure: (Part 1) To a stirred solution of Cinchona alkaloid (either Quinine, Quinidine, Cinchonine or Cinchonidine) (1 equiv.) in THF (0.1 M) was added the required arylmethyl halide compound (1.2 equiv.) at room temperature. The reaction mixture was refluxed overnight, cooled to room temperature and all volatiles were removed invacuo. The residue was then dissolved in CH2Cl2 (typically 2 mL for 1 mmol of starting material) and the resulting solution was added dropwise onto Et2O (typically 30 mL for 1 mmol of starting material) with vigorous stirring. The resulting precipitate was then filtered, washed thoroughly with Et2O, and further dried under high vacuum for 2 hours, yielding the intermediate alcohol product in an excellent yield. (Part2) This product (1 equiv.) was dissolved in CH2Cl2 (0.2 M). Methyl iodide (3 equiv.) and an aqueous sodium hydroxide solution (50 percentw, 5 equiv.) were successively added at room temperature. The reaction mixturewas stirred at room temperature for 4 h, before water (typically 20 mL for 1 mmol of starting material) was added to quench the reaction. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo (N.B: washing with brine is prohibited to avoid the I/Cl anion exchange). Purification by column chromatography on silica gel, eluting with MeOH/Acetone/CH2Cl2 (0:10:90 to 10:10:90), afforded the desired Cinchona alkaloid quaternary ammonium salt in a moderate to excellent yield.

Molecular Weight:421.0
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:420.1968412
Monoisotopic Mass:420.1968412
Topological Polar Surface Area:33.1
Heavy Atom Count:30
Complexity:573
Defined Atom Stereocenter Count:4
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes