Our protocol details a convenient one-pot preparation and copper-mediated conjugate addition of functionalized monoorganozinc bromides to cyclic alpha-beta-unsaturated carbonyls for the synthesis of quaternary centers in high yield. A significant advantage to this method involves the use of dimethylacetamide to facilitate organozinc formation from widely accessible functionalized organobromides. To begin, add zinc, dust, DMA, and iodine to a flame-dried 50-milliliter Schlenk reaction flask containing a stir bar under argon.
Stir the suspension at ambient temperature until the brownish-orange color completely dissipates to a gray suspension. Add ethyl 4-bromobutyrate to the gray suspension. Immerse the flask in an 80-degree Celsius oil bath with vigorous stirring until consumption of the organobromide is observed by gas chromatography or GC analysis.
Briefly dip a disposable glass Pasteur pipette into the reaction mixture and remove from the flask. Rinse the aliquot with approximately 0.5 milliliters of diethyl ether into a two-milliliter vial containing approximately 0.5 milliliters of saturated ammonium chloride. Vigorously shake the vial and analyze the organic layer by GC.After cooling the monoorganozinc reagent to ambient temperature the reagent can be stored for several hours to overnight under inert atmosphere with minimal impact on the yield of the conjugate addition product.
For monoorganozinc bromide conjugate addition to alpha-beta unsaturated ketones first cool the organozinc suspension in an ice water bath for approximately five minutes. Then add copper bromide dimethyl sulfide and additional DMA and stir the reaction for 10 minutes. Next add chlorotrimethylsilane to the cooled suspension followed by 3-methyl-2-cyclohexanone.
Remove the cooling bath after approximately 30 minutes and monitor the reaction until the alpha-beta unsaturated ketone is consumed by TLC analysis for up to 24 hours. Add acetic acid to the completed conjugate addition reaction to hydrolyze the intermediate silyl enol ether into the ketone product. Monitor the progress of hydrolysis in 15-minute intervals by TLC analysis as before.
In the event that silyl enol ether remains after one hour add tetrabutylammonium fluoride to facilitate complete hydrolysis as evident by TLC. Add one molar hydrochloric acid to the reaction flask and mix well. Then transfer the reaction contents into a 250-milliliter separatory funnel.
Rinse the flask with diethyl ether and water, adding the rinses to the separatory funnel. Gently shake the contents of the funnel, venting between each mixing, and allow the layers to separate. Drain the bottom aqueous layer into a 125-milliliter Erlenmeyer flask and then drain the organic layer into a separate 250-milliliter Erlenmeyer flask.
Return the aqueous layer to the separatory funnel and extract with four separate portions of diethyl ether adding each organic extraction to the organic-containing Erlenmeyer flask. Add the combined organic extractions to the separatory funnel and wash with saturated aqueous sodium bicarbonate. Drain the aqueous washing into the aqueous-containing Erlenmeyer flask.
Now wash the combined organic extractions with saturated aqueous sodium chloride. After draining the second aqueous washing into the aqueous-containing Erlenmeyer flask, drain the final organic layer into a dry 250-milliliter Erlenmeyer flask. Dry the organic layer over magnesium sulfate and vacuum filter into a 250-milliliter round bottom flask using a glass fritted Buchner funnel.
Rinse the solids on the frit with a small portion of additional diethyl ether. Concentrate the filtrate under reduced pressure using a rotary evaporator. Place the flask with remaining residue under high vacuum for at least 10 minutes.
Analyze a sample of the crude residue by proton NMR using deuterated chloroform. To purify the crude oil by automated flash chromatography dry load the sample by dissolving the crude oil in a minimal amount of diethyl ether. Then transfer this elution to a prepackaged silica gel cartridge.
Apply reduced pressure to the bottom of the loading column for approximately five minutes to remove the excess solvent. Elute the sample using a prepackaged silica gel column with a gradient of ethyl acetate in hexanes, collecting the column effluent in test tubes. Assay fraction purity using TLC analysis as before.
Combine and rinse all fractions containing the desired quaternary ketone in a tared round bottom flask. Finally, concentrate the solution under reduced pressure on a rotary evaporator and remove the final volatiles under high vacuum for at least 30 minutes. Obtain a final mass of the flask and analyze a sample of the purified product by proton NMR using deuterated chloroform.
The conjugate addition product, ethyl 4-butanoate was isolated as a clear colorless oil using this efficient one-pot protocol. Analysis of proton and carbon NMR spectra confirm the structure and purity. Of specific note in the proton spectrum analysis is the presence of a two-proton AB quartet at a chemical shift of 2.15 ppm, indicating that the diastereotopic C2 hydrogens spin couple.
A three-proton singlet at a chemical shift of 0.94 ppm represents the Z1 quaternary methyl group. A collection of cyclic ketone addition products with beta quaternary centers were prepared in good to excellent yields using this simple and efficient one-pot protocol. All reaction products were analyzed by proton and carbon NMR, as well as high resolution mass spectrometry and found to be of high purity.
In addition to the incorporation of ester, nitrogen, and halide functionality this reaction protocol furnishes products with various ring sizes and high levels of stereoselectivity when using chiral alpha, beta-unsaturated ketones. It is evident from these examples that the favored pathway involves delivery of the organic fragment to the alkene face opposite to non-hydrogen groups at the gamma and delta position of the alpha-beta unsaturated ketone. It is important to verify complete zinc insertion of the organobromide due to the diminished yields obtained with decreased equivalents of monoorganozinc reagent.
The reagents and solvents used in this procedure are generally flammable and mildly toxic. Reactions should be carried out in fume hood using appropriate personal protective equipment.
