Synthesis of (R)‐warfarin

Objective

To demonstrates a one-step synthesis of warfarin using organocatalysis.

Synthesis of (R)‐warfarin organocatalysis

Background

Organocatalysis is an area of organic chemistry that has been rapidly expanding in recent years, with significant interest in enantioselective organocatalytic reactions. Organocatalysts containing an amine functionality typically proceed via an iminium or enamine intermediate, which is then attacked by an incoming nucleophile. These reactions often achieve extremely high levels of enantio- or diastereoselectivity. This experiment demonstrates the one-step synthesis of warfarin, an anticoagulant widely used to treat patients with deep vein thrombosis or pulmonary embolism. Both enantiomers of warfarin can be prepared; to synthesize (S)-warfarin, (S,S)-1,2-diphenylethylenediamine should be used as the catalyst.

Experimental procedure

In a vial, measure 4-hydroxycoumarin and add THF, followed by 4-phenylbuten-2-one, (R,R)-1,2-diphenylethylenediamine, and acetic acid. Allow the reaction mixture to stand at room temperature for one week. During this time, the color of the reaction should change from peach/pink to clear yellow. Carry out TLC analysis by using a TLC plate pre-coated with silica, eluting with dichloromethane CH2Cl2. Observe the developed plate under UV light, and stain the spots with anisaldehyde. Record the Rf values. Remove the solvent using a rotary evaporator or by using a stream of air to give an orange foam. Dissolve the residue in the minimum amount of boiling acetone, and add boiling water dropwise until the solution becomes significantly cloudy. Continue heating to redissolve these crystals, adding more acetone if necessary. Slowly allow the reaction mixture to cool to room temperature, then cool in an ice bath. Collect the crystalline product by vacuum filtration, rinsing carefully with a small amount of a 4:1 mixture of acetone/water. Allow the crystals to dry, and calculate the yield of the product. Record the yield, melting point, and IR and 1H NMR spectra (CDCl3) of your product.

References

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