The authors thank the American Chemical Society (ACS) Petroleum Research Fund Undergraduate New Investigator Program (Award No. 58488-UNI1), the ACS and Pfizer (SURF support to T.J.F.), Bucknell University (research fellowships to T.J.F.), and the Department of Chemistry (research fellowship to K.M.T.) for generous support of this work. Dr. Peter M. Findeis and Brian Breczinski are acknowledged for experimental and instrumentation assistance.

CAUTION: Consult Material Safety Data Sheets (MSDS) prior to the use of the chemicals in this procedure. Use appropriate personal protective equipment (PPE), including safety glasses, a lab coat, and nitrile or butyl gloves as many of the reagents and solvents are corrosive, toxic, or flammable. Carry out all reactions in a fume hood. It is necessary to flame-dry glassware and use an inert atmosphere (nitrogen or argon) for this protocol. Liquids used in the first two steps of the protocol are syringe transferred.
<p...

<ol>
	<li>Hawner, C., Alexakis, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Metal-Catalyzed+Asymmetric+Conjugate+Addition+Reaction:+Formation+of+Quaternary+Stereocenters.">Metal-Catalyzed Asymmetric Conjugate Addition Reaction: Formation of Quaternary Stereocenters.</a> Chemical Communications. 46 (39), 7295-7306 (2010).</li><li>Quasdorf, K. W., Overman, L. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catalytic+Enantioselective+Synthesis+of+Quaternary+Carbon+Stereocentres.">Catalytic Enantioselective Synthesis of Quaternary Carbon Stereocentres.</a> Nature. 516 (7530), 181-191 (2014).</li><li>Knochel, P., Leuser, H., Cong, L. -. Z., Perrone, S., Kneisel, F. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Polyfunctional+Zinc+Organometallics+for+Organic+Synthesis.">Polyfunctional Zinc Organometallics for Organic Synthesis.</a> Handbook of Functionalized Organometallics. , 251-346 (2005).</li><li>Dagousset, G., Fran&#231;ois, C., Le&#243;n, T., Blanc, R., Sansiaume-Dagousset, E., Knochel, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preparation+of+Functionalized+Lithium,+Magnesium,+Aluminum,+Zinc,+Manganese,+and+Indium+Organometallics+From+Functionalized+Organic+Halides.">Preparation of Functionalized Lithium, Magnesium, Aluminum, Zinc, Manganese, and Indium Organometallics From Functionalized Organic Halides.</a> Synthesis. 46 (23), 3133-3171 (2014).</li><li>Kim, J. H., Ko, Y. O., Bouffard, J., Lee, S. -. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advances+in+Tandem+Reactions+with+Organozinc+Reagents.">Advances in Tandem Reactions with Organozinc Reagents.</a> Chemical Society Reviews. 44 (8), 2489-2507 (2015).</li><li>Benischke, A. D., Ellwart, M., Becker, M. R., Knochel, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Polyfunctional+Zinc+and+Magnesium+Organometallics+for+Organic+Synthesis:+Some+Perspectives.">Polyfunctional Zinc and Magnesium Organometallics for Organic Synthesis: Some Perspectives.</a> Synthesis. 48 (8), 1101-1107 (2016).</li><li>Hird, A. W., Hoveyda, A. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catalytic+Enantioselective+Alkylations+of+Tetrasubstituted+Olefins.+Synthesis+of+All-Carbon+Quaternary+Stereogenic+Centers+Through+Cu-Catalyzed+Asymmetric+Conjugate+Additions+of+Alkylzinc+Reagents+to+Enones.">Catalytic Enantioselective Alkylations of Tetrasubstituted Olefins. Synthesis of All-Carbon Quaternary Stereogenic Centers Through Cu-Catalyzed Asymmetric Conjugate Additions of Alkylzinc Reagents to Enones.</a> Journal of the American Chemical Society. 127 (43), 14988-14989 (2005).</li><li>Lee, K. -. S., Brown, M. K., Hird, A. W., Hoveyda, A. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Practical+Method+for+Enantioselective+Synthesis+of+All-Carbon+Quaternary+Stereogenic+Centers+Through+NHC-Cu-Catalyzed+Conjugate+Additions+of+Alkyl-+and+Arylzinc+Reagents+to+&#946;-Substituted+Cyclic+Enones.">A Practical Method for Enantioselective Synthesis of All-Carbon Quaternary Stereogenic Centers Through NHC-Cu-Catalyzed Conjugate Additions of Alkyl- and Arylzinc Reagents to &#946;-Substituted Cyclic Enones.</a> Journal of the American Chemical Society. 128 (22), 7182-7184 (2006).</li><li>Brown, M. K., May, T. L., Baxter, C. A., Hoveyda, A. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=All-Carbon+Quaternary+Stereogenic+Centers+by+Enantioselective+Cu-Catalyzed+Conjugate+Additions+Promoted+by+a+Chiral+N-Heterocyclic+Carbene.">All-Carbon Quaternary Stereogenic Centers by Enantioselective Cu-Catalyzed Conjugate Additions Promoted by a Chiral N-Heterocyclic Carbene.</a> Angewandte Chemie International Edition. 46 (7), 1097-1100 (2007).</li><li>Knochel, P., Yeh, M. C. P., Berk, S. C., Talbert, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+and+Reactivity+Toward+Acyl+Chlorides+and+Enones+of+the+New+Highly+Functionalized+Copper+Reagents+RCu(CN)ZnI.">Synthesis and Reactivity Toward Acyl Chlorides and Enones of the New Highly Functionalized Copper Reagents RCu(CN)ZnI.</a> The Journal of Organic Chemistry. 53 (10), 2390-2392 (1998).</li><li>Yeh, M. C. P., Knochel, P., Butler, W. M., Berk, S. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=1,4-Additions+of+the+Highly+Functionalized+Copper+Reagents+RCu(CN)-ZnI&#8226;2+BF3+to+Trisubstituted+Enones.+A+New+BF3+Promoted+Cyclization+Reaction.">1,4-Additions of the Highly Functionalized Copper Reagents RCu(CN)-ZnI&#8226;2 BF3 to Trisubstituted Enones. A New BF3 Promoted Cyclization Reaction.</a> Tetrahedron Letters. 29 (51), 6693-6696 (1988).</li><li>Knochel, P., Chou, T. S., Chen, H. G., Yeh, M. C. P., Rozema, M. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nucleophilic+Reactivity+of+Zinc+and+Copper+Carbenoids.+Part+II.">Nucleophilic Reactivity of Zinc and Copper Carbenoids. Part II.</a> The Journal of Organic Chemistry. 54 (22), 5202-5204 (1989).</li><li>Tamaru, Y., Tanigawa, H., Yamamoto, T., Yoshida, Z. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper(I)-Promoted+Michael-Addition+Reaction+of+Organozincs+of+Esters,+Nitriles,+and+&#945;-Amino+Acids.">Copper(I)-Promoted Michael-Addition Reaction of Organozincs of Esters, Nitriles, and &#945;-Amino Acids.</a> Angewandte Chemie International Edition. 28 (3), 351-353 (1989).</li><li>Fulton, T. J., Alley, P. L., Rensch, H. R., Ackerman, A. M., Berlin, C. B., Krout, M. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Access+to+Functionalized+Quaternary+Stereocenters+via+the+Copper-Catalyzed+Conjugate+Addition+of+Monoorganozinc+Bromide+Reagents+Enabled+by+N,N-Dimethylacetamide.">Access to Functionalized Quaternary Stereocenters via the Copper-Catalyzed Conjugate Addition of Monoorganozinc Bromide Reagents Enabled by N,N-Dimethylacetamide.</a> The Journal of Organic Chemistry. 83 (23), 14723-14732 (2018).</li><li>Krasovskiy, A., Malakhov, V., Gavryushin, A., Knochel, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Efficient+Synthesis+of+Functionalized+Organozinc+Compounds+by+the+Direct+Insertion+of+Zinc+into+Organic+Iodides+and+Bromides.">Efficient Synthesis of Functionalized Organozinc Compounds by the Direct Insertion of Zinc into Organic Iodides and Bromides.</a> Angewandte Chemie International Edition. 45 (36), 6040-6044 (2006).</li><li>Huo, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Highly+Efficient,+General+Procedure+for+the+Preparation+of+Alkylzinc+Reagents+from+Unactivated+Alkyl+Bromides+and+Chlorides.">Highly Efficient, General Procedure for the Preparation of Alkylzinc Reagents from Unactivated Alkyl Bromides and Chlorides.</a> Organic Letters. 5 (4), 423-425 (2003).</li><li>Still, W. C., Kahn, M., Mitra, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+Chromatographic+Technique+for+Preparative+Separations+with+Moderate+Resolution.">Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution.</a> The Journal of Organic Chemistry. 43 (14), 2923-2925 (1978).</li><li>Knopff, O., Alexakis, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tandem+Asymmetric+Conjugate+Addition-Silylation+of+Enantiomerically+Enriched+Zinc+Enolates.+Synthetic+Importance+and+Mechanistic+Implications.">Tandem Asymmetric Conjugate Addition-Silylation of Enantiomerically Enriched Zinc Enolates. Synthetic Importance and Mechanistic Implications.</a> Organic Letters. 4 (22), 3835-3837 (2002).</li></ol>

The authors have no competing financial interests.

The method detailed herein was developed to harness mild functionalized monoorganozinc reagents in a simple and efficient conjugate addition reaction for the synthesis of &#946;-quaternary ketones14. Excellent yields and significantly improved catalyst efficiencies were observed through the use of the polar, aprotic solvent DMA with TMSCl. Monoorganozinc formation is aided by DMA, facilitating the direct zinc insertion into readily available alkyl bromides to create a broad scope of functionalized...

The formation of carbon-carbon bonds is arguably the most important and powerful transformation in organic chemistry. The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls comprises one of the most versatile methods for the construction of C-C bonds, especially in the challenging generation of all-carbon quaternary centers1,2. Despite the central importance of the conjugate addition of organometallic reagents to the formation of quaternary centers, few methodologies address the challenge of incorporating sensitive functional groups in these reactions. Indeed, in the majority of these transformations, highly reactive organolithium, Grignard, or diorganozinc reagents are the nucleophiles of choice. These reactive organometallics, however, are incompatible with many sensitive functional groups, thereby limiting the complexity of both the &#945;,&#946;-unsaturated carbonyl and organometallic reagent, often necessitating the use of protecting groups or alternative strategies in multi-step synthesis.
Monoorganozinc reagents are an attractive class of organometallic reagents which have garnered widespread attention for their mild reactivity and enhanced functional group compatibility3,4,5,6. In spite of their exceptional functional group tolerance and trivial preparation from organohalides, there are few examples of monoorganozinc reagents in the conjugate addition to &#160;&#946;,&#946;-disubstituted &#945;,&#946;-unsaturated carbonyls to generate quaternary centers7,8,9. Furthermore, these transformations typically require stoichiometric quantities of toxic cyanocuprate reagents with one report demonstrating minimal catalyst turnover10,11,12,13. The objective of our study is to establish a simple and practical catalytic method for the conjugate addition of functionalized monoorganozinc reagents to &#945;,&#946;-unsaturated carbonyls to generate all-carbon quaternary centers. Toward this end, we have developed a protocol utilizing N,N-dimethylacetamide (DMA) as a solvent with chlorotrimethylsilane (TMSCl) as a Lewis acid which enables a &#8220;one-pot&#8221; copper catalyzed (20 mol %) conjugate addition of functionalized monoorganozinc reagents to &#945;,&#946;-unsaturated carbonyls to generate a broad scope of all-carbon quaternary centers in high yield14.
The utilization of DMA as a solvent has several notable advantages over methods reported in the literature. DMA improves the efficiency of zinc insertion into organohalides which obviates the requirement for expensive and hygroscopic additives such as LiCl employed in ethereal solvent systems15. This also expands the scope of direct zinc insertion from sensitive, often commercially unavailable organoiodides to more stable and widely accessible organobromides16. The protocol detailed herein generates alkyl monoorganozinc reagents (2) from diverse organobromides, which are used in situ in the formation of a reactive cuprate complex that engages cyclic &#945;,&#946;-unsaturated ketones in a conjugate addition reaction (Figure 1). DMA also enables the reaction to proceed with cheaper and less toxic copper sources such as CuBr&#183;DMS, eliminating stoichiometric toxic waste generated with CuCN utilized in other reports10,11,12,13. Our standard reaction conditions provide access to a broad scope of &#946;-quaternary ketones (5) with both five-, six-, and seven-membered ring conjugate acceptors obtained via the hydrolysis of an intermediate silyl enol ether (4). The intermediate silyl enol ether was observed to be moderately stable and could be isolated in excellent yield utilizing a modified workup procedure.

<table>
	<tbody>
		<tr>
			<td>Ammonium Chloride</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Biotage Isolera One Flash Chromatography System</td>
			<td>Biotage</td>
			<td>ISO-ISW</td>
			<td>UV/vis detection (254, 280, 200-400nm)</td>
		</tr>
		<tr>
			<td>Chloroform-D, (D, 99.8%)</td>
			<td>Cambridge Isotope Laboratories</td>
			<td>DLM-7</td>
			<td></td>
		</tr>
		<tr>
			<td>Copper (I) bromide dimethyl sulfide complex , 99%</td>
			<td>Sigma Aldrich</td>
			<td>230502</td>
			<td>Air and moisture sensitive</td>
		</tr>
		<tr>
			<td>Diethyl Ether, anhydrous, 99%</td>
			<td>EMD Chemicals</td>
			<td>MEX01906</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>Ethyl 4-bromobutyrate</td>
			<td>Oakwood</td>
			<td>139400</td>
			<td></td>
		</tr>
		<tr>
			<td>Ethyl Acetate, 99.9%</td>
			<td>Fisher</td>
			<td>E145-500</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>Glacial Acetic Acid</td>
			<td>Oakwood</td>
			<td>O35907</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>HCl</td>
			<td></td>
			<td></td>
			<td>1 M aq</td>
		</tr>
		<tr>
			<td>Hexanes, 98.5%</td>
			<td>EMD Chemicals</td>
			<td>HX0299</td>
			<td>ACS</td>
		</tr>
		<tr>
			<td>HP 6890 Series GC</td>
			<td>HP</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>HP-1 GC Column</td>
			<td>Agilent</td>
			<td>19091-60312</td>
			<td>0.2 mm x 0.33 um, 12 m, 7 inch cage</td>
		</tr>
		<tr>
			<td>Iodine</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Magnesium Sulfate, anhydrous, 98%</td>
			<td>EMD Chemicals</td>
			<td>MX0075</td>
			<td></td>
		</tr>
		<tr>
			<td>Mehtyl enone</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>N,N-Dimethylacetamide, anhydrous, 99%</td>
			<td>Alfa Aesar</td>
			<td>A10924</td>
			<td>Dried over 3 &#197;ms</td>
		</tr>
		<tr>
			<td>Silica gel</td>
			<td>VWR</td>
			<td>86306-350</td>
			<td>60 &#197;, 40-60 um</td>
		</tr>
		<tr>
			<td>Sodium Bicarbonate</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium Chloride</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Tetra-n-butylammonium fluoride</td>
			<td>Oakwood</td>
			<td>O43479</td>
			<td>1 M in THF</td>
		</tr>
		<tr>
			<td>Thin-layer chromatography plates</td>
			<td>EMD Milipore</td>
			<td>115341</td>
			<td>6.5 x 2.2 cm2, 60 g F254 precoated plates (9.5-11.5 um particle size)</td>
		</tr>
		<tr>
			<td>Trimethyl silyl chloride, 99%</td>
			<td>Sigma Aldrich</td>
			<td>386529</td>
			<td>Air sensitive</td>
		</tr>
		<tr>
			<td>Zinc</td>
			<td></td>
			<td></td>
			<td>Powder, HCl-washed</td>
		</tr>
	</tbody>
</table>

efficient synthesis of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc bromides

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the preparation of all-carbon quaternary centers. Though conjugate additions of organometallic reagents are typically performed utilizing highly reactive organolithium or Grignard reagents, organozinc reagents have garnered attention for their enhanced chemoselectivity and mild reactivity. Despite numerous recent advances with more reactive diorganozinc and mixed diorganozinc reagents, the generation of all-carbon quaternary centers via the conjugate addition of functionalized monoorganozinc reagents remains a challenge. This protocol details a convenient and mild &#8220;one-pot&#8221; preparation and copper mediated conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to afford a broad scope of all-carbon quaternary centers in generally excellent yield and diastereoselectivity. Key to the development of this technology is the utilization of DMA as a reaction solvent with TMSCl as a Lewis acid. Notable advantages to this methodology include the operational simplicity of the organozinc reagent preparation afforded by the utilization of DMA as a solvent, as well as an efficient conjugate addition mediated by various Cu(I) and Cu(II) salts. Moreover, an intermediate silyl enol ether can be isolated utilizing a modified workup procedure. The substrate scope is limited to cyclic unsaturated ketones, and the conjugate addition is impeded by stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents. Conjugate additions to five- and seven-membered rings were effective, albeit in lower yields compared with six-membered ring substrates.

Conjugate addition product ethyl 4-(1-methyl-3-oxocyclohexyl)butanoate (21) was isolated as a clear, colorless oil (1.0372 g, 4.583 mmol, 92% yield) using this efficient one-pot protocol. 1H and 13C NMR spectra are presented in Figure 2 and Figure 3 to confirm the structure and purity. Of specific note in the 1H spectrum analysis is the presence of a two proton AB quartet at &#948...

Watch this Scientific Journal Video about Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides at JoVE.com

Efficient Synthesis of All-Carbon Quaternary Centers via the Conjugate Addition of Functionalized Monoorganozinc Bromides

A simple and practical protocol for the efficient conjugate addition of functionalized monoorganozinc bromides to cyclic &#945;,&#946;-unsaturated carbonyls to furnish all-carbon quaternary centers was developed.

The conjugate addition of organometallic reagents to &#945;,&#946;-unsaturated carbonyls represents an important method to generate C&#8211;C bonds in the ...

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.

efficient-synthesis-all-carbon-quaternary-centers-via-conjugate

Research

JoVE Journal

Chemistry

9.1K ビュー.  California Institute of Technology. 我々のプロトコルは、高収率の第四級中心の合成のための環状α-β不飽和カルボニルへの機能的なモノオルガン亜鉛臭化物の便利なワンポット調製および銅媒介コンジュゲートの添加を詳述する。この方法に対する重要な利点は、広く利用できる官能化された有機臭化物から有機亜鉛形成を促進するためにジメチルアセトアミドを使用することを含む。まず、アルゴン下...