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.
1. Functionalized monoorganozinc bromide formation16
<ol>
	<li>Add zinc dust (0.8173 g, 12.50 mmol, 2.5 equiv), DMA (6.0 mL), and I2 (126.9 mg, 0.500 mmol, 0.10 equiv) to a flame-dried 50 mL 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. 
	CAUTION: DMA is flammable, acutely toxic, and a mild irritant.</li>
	<li>Add ethyl 4-bromobutyrate (6; 1.43 mL, 10.0 mmol, 2.0 equiv) to the gray suspension. Immerse the flask in an 80 &#176;C oil bath with vigorous stirring until consumption of the organobromide is observed by gas chromatography (GC) analysis. 
	CAUTION: Ethyl 4-bromobutyrate is flammable and a mild irritant.
	<ol>
		<li>Briefly dip a disposable glass Pasteur pipet into the reaction mixture, remove from the flask and rinse the aliquot with ca. 0.5 mL of diethyl ether (Et2O) into a 2 mL vial containing ca. 0.5 mL of saturated NH4Cl. Vigorously shake the vial and analyze the organic layer by GC. 
		NOTE: Reaction progress is determined by comparing the disappearance of the organobromide peak to the appearance of the protonated organozinc reagent, which typically has a shorter retention time. 
		CAUTION: Et2O is flammable and acutely toxic.</li>
	</ol>
	</li>
	<li>Cool the monoorganozinc reagent to ambient temperature. The remainder of this conjugate addition protocol can be paused at this stage for several hours to overnight under inert atmosphere with minimal impact on the yield of the conjugate addition product.</li>
</ol>
2. Monoorganozinc bromide conjugate addition to &#945;,&#946;-unsaturated ketones
<ol>
	<li>Cool the organozinc suspension in an ice/H2O bath for ca. 5 min, and then add CuBr&#183;DMS (205.6 mg, 1.000 mmol, 0.20 equiv) and additional DMA (10.5 mL, 0.30 M overall with respect to unsaturated ketone), and stir the reaction for ca. 10 min.</li>
	<li>Add TMSCl (1.52 mL, 12.0 mmol, 2.4 equiv) to the cooled suspension, followed by 3-methyl-2-cyclohexenone (13; 567 &#181;L, 5.00 mmol, 1.0 equiv). Remove the cooling bath after ca. 30 min and monitor the reaction until the a,b-unsaturated ketone is consumed by TLC analysis, or up to 24 h. 
	NOTE: TLC analysis is performed with silica-coated glass plates and developed with 4:1 hexanes&#8211;ethyl acetate. Rf values: unsaturated ketone 13 = 0.15; silyl enol ether 37 = 0.61; ketone product 21 = 0.21. Visualization is achieved by UV-quenching at 254 nm, followed by p-anisaldehyde staining. 
	CAUTION: TMSCl is flammable, acutely toxic, a skin irritant, and corrosive. 3-methyl-2-cyclohexenone is flammable and acutely toxic.</li>
</ol>
3. Extraction work-up and purification
<ol>
	<li>Add acetic acid (1.5 mL, ca. 5 equiv) to the completed conjugate addition reaction to hydrolyze the intermediate silyl enol ether into the ketone product. Monitor the progress of hydrolysis in ca. 15 min intervals by TLC analysis using conditions from step 2.2. 
	CAUTION: Acetic acid is flammable and corrosive.
	<ol>
		<li>In the event that the silyl enol ether remains after 1 h, add tetrabutylammonium fluoride (TBAF; 1 M solution in THF, 0.5&#8211;1.0 equiv at a time) to facilitate complete hydrolysis as evident by TLC.</li>
	</ol>
	</li>
	<li>Add 1 M HCl (15 mL) to the reaction flask, mix well, and then transfer the reaction contents into a 250 mL separatory funnel. Rinse the flask with Et2O (20 mL) and H2O (15 mL), 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 mL Erlenmeyer flask, and then drain the organic layer into a separate 250 mL Erlenmeyer flask.</li>
	<li>Return the aqueous layer to the separatory funnel and extract with four separate portions of Et2O (4 x 30 mL), adding each organic extraction to the organic-containing Erlenmeyer flask.</li>
	<li>Add the combined organic extractions to the separatory funnel and sequentially wash with saturated aqueous NaHCO3 (25 mL), then saturated aqueous NaCl (25 mL). Drain each aqueous washing into the aqueous-containing Erlenmeyer flask, and drain the final organic layer into a dry 250 mL Erlenmeyer flask.</li>
	<li>Dry the organic layer over MgSO4 and vacuum filter into a 250 mL round bottom flask using a glass-fritted Buchner funnel. Rinse the solids on the frit with a small portion of additional Et2O.</li>
	<li>Concentrate the filtrate under reduced pressure using a rotary evaporator. Place the flask with remaining residue under high vacuum (ca. 75&#8211;200 mtorr) for at least 10 min. Analyze a sample of the crude residue by 1H NMR using CDCl3.</li>
	<li>Purify the crude oil by automated flash chromatography using a silica gel (SiO2) stationary phase with a dry-loaded sample and elute with ethyl acetate in hexanes.
	<ol>
		<li>Dry-load the sample by dissolving the crude oil in a minimal amount of Et2O, and then transfer this solution to a prepacked SiO2 cartridge (25 g). Apply a reduced pressure to the bottom of the loading column for ca. 5 min to remove the excess solvent.</li>
		<li>Elute the sample using a prepacked SiO2 column (100 g) with a gradient of ethyl acetate in hexanes (5% &#8594; 25%), collecting the column effluent in test tubes.</li>
		<li>Assay fraction purity using TLC analysis (conditions in Step 2.2). Combine and rinse all fractions containing the desired quaternary ketone into a tared round bottom flask.</li>
	</ol>
	</li>
	<li>Concentrate the solution under reduced pressure on a rotary evaporator and remove the final volatiles under high vacuum for at least 30 min. Obtain a final mass of the flask and analyze a sample of the purified product by 1H NMR using CDCl3. 
	CAUTION: Hexanes and ethyl acetate are flammable. SiO2 powder is a respiratory irritant.</li>
</ol>

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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. -. 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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. 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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. 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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 reagents16.
Monoorganozinc bromide formation is the most important step in this protocol. We have obtained modest to excellent success for conjugate addition reactions when the conversion to the organozinc reagent is quantitative, given the proper equivalence of catalyst and TMSCl. Organobromides with increased substitution near the C-Br bond undergo zinc insertion at a diminished rate compared to the typical 3 h time frame, including substrate 11 (28 h) and substrate 12 (80 h). However, stabilized benzyl organozinc reagents from 9 and 10 are formed at an increased rate (ca. 1 h) at 21-40 &#176;C. The corresponding functionalized cuprate reagents perform well in conjugate addition reactions (24, 25, 26, and 27, Figure 4) despite this temperature difference.
Upon successful conjugate addition, the silyl enol ether intermediate is hydrolyzed with acid to afford the final ketone product. Acetic acid was the optimal organic-soluble Br&#248;nsted acid to facilitate this mild hydrolysis step when compared to aqueous HCl. Silyl enol ethers that are recalcitrant to hydrolysis can be readily cleaved to ketone products with TBAF. Notably, the synthetically useful18 silyl enol intermediate 37 could be isolated in 74% yield using this one-pot protocol by substituting the acid workup with NaHCO3 (Table 1, entry 7).
Challenging purifications can result from incomplete conversion of the unsaturated ketone, owing to the similar Rf values of the substrate and ketone product. The modest volatility of the majority of unsaturated ketones used in this study enable their removal through prolonged exposure (&#62; 1 h) to high vacuum.
The broad scope of organobromides and unsaturated ketones for this one-pot protocol yields an array of functionalized &#946;-quaternary ketones14. This method is currently limited to cyclic unsaturated ketones, as we have not explored acyclic substrates. Quaternary ketones have been generated from unsaturated five- and seven-membered rings, albeit in modest yield8 presumably due to differences in overlap of the conjugated system. The conjugate addition also does not proceed with several stabilized (e.g., allyl, enolate, homoenolate) and sterically encumbered (e.g., neopentyl, o-aryl) monoorganozinc reagents14. We are currently investigating the reactivity of monoorganozinc reagents with respect to Lewis acid and Lewis base additives, in an effort to improve the reaction efficiency and incorporate a more significant scope of organobromides and unsaturated ketones. Excellent yields and selectivities are maintained with a marked improvement in catalyst efficiency when using monoorganozinc reagents that have been filtered from zinc solids after insertion14. Moreover, various Cu(I) and Cu(II) salts facilitate efficacious conjugate additions when coupled with filtered monoorganozinc reagents.
In summary, we have described an efficient one-pot protocol for the conjugate addition of functionalized monoorganozinc reagents in the preparation of functionalized &#946;-quaternary ketones. This protocol comprises a convenient method to explore the feasibility of various organobromide and unsaturated carbonyl combinations (Figure 1) toward these valuable products.

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 &amp;Aring;ms</td></tr><tr><td>Silica gel</td><td>VWR</td><td>86306-350</td><td>60 &amp;Aring;, 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; 2.15 ppm, indicating that the diastereotopic C2 hydrogens spin couple. A three-proton singlet at &#948;&#160;0.94 ppm represents the C1 quaternary methyl group.
Ethyl 4-(1-methyl-3-oxocyclohexyl)butanoate (21). Rf = 0.21 (4:1 hexanes/ethyl acetate); 1H NMR (400 MHz, CDCl3): &#948; 4.13 (q, J = 7.1 Hz, 2H), 2.32&#8722;2.23 (m, 4H), 2.15 (ABq, &#916;&#948;AB = 0.06, JAB = 13.5 Hz, 2H), 1.87 (quintet, J = 6.4 Hz, 2H), 1.60 (dtt, J = 23.3, 15.4, 7.6 Hz, 4H), 1.34&#8722;1.21 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H), 0.94 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): &#948; 211.3, 172.9, 59.9, 53.4, 40.7, 40.6, 38.2, 35.3, 34.3, 24.7, 21.8, 18.7, 14.0; IR (ATR): 2951, 2939, 2873, 1730, 1708, 1374, 1178, 1025 cm-1; HRMS (DART+) m/z: [M + H]+ calcd for C13H23O3 227.1642, found 227.1640.
A collection of cyclic ketone addition products with &#946;-quaternary centers were prepared in good to excellent yields using this simple and efficient one-pot protocol (Figure 4)14. All reaction products were analyzed by 1H and 13C NMR, as well as high-resolution mass spectrometry (HRMS), and found to be of high purity. In addition to the incorporation of ester (21), nitrogen (22, 24), and halide (23, 27) functionality, this reaction protocol furnishes products with various ring sizes (29-31) and high levels of stereoselectivity ((&#177;)-32-(&#177;)-35) when using chiral &#945;,&#946;-unsaturated ketones ((&#177;)-17-(&#177;)-20). Diastereomer ratios are determined by routine integration of select peaks in the product 1H spectrum with the major diastereomer shown14. It is evident from these examples that the favored pathway involves delivery of the organic fragment to the alkene face opposite to non-H groups at the &#947;- and &#948;-position of the &#945;,&#946;-unsaturated ketone.
Monoorganozinc formation on this scale generally requires heating at 80 &#176;C for 2.5-3 h and yields a colorless to pale-yellow suspension with zinc dust remaining. GC analysis provides an ideal method for the detection of organobromide reagents during this step owing to their challenging visualization by TLC analysis. Progress of the conjugate addition (Step 2.2) and enol ether hydrolysis (Step 3.1) are monitored by TLC analysis. Unsaturated ketone 13 (Rf = 0.15, 4:1 hexanes-ethyl acetate) is UV-active and stains, whereas the intermediate silyl enol ether (Rf = 0.61) and ketone product 21 (Rf = 0.21) stain only. Incomplete hydrolysis of the enol ether is generally indicated by the presence of a singlet at &#948; 4.64 in the 1H NMR spectrum (Step 3.6). Standard flash chromatography is adequate for the purification of conjugate addition products17.
Optimal yields of the conjugate addition products are obtained when using the established reagent equivalence for the monoorganozinc (2.0), copper catalyst (20 mol %), and Lewis acid (2.4) parameters. A diminished 72% yield of 21 was observed with a decrease in CuBr&#183;DMS to 10 mol% (Table 1, entries 1-3). Reducing the monoorganozinc bromide (36) or TMSCl equivalence to 1.2 also resulted in a modest decrease in the production of 21 (entries 4 and 5). Notably, the conjugate addition does not proceed without CuBr&#183;DMS or TMSCl (entries 3 and 6).
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/59775/59775fig1v2.jpg" /> 
Figure 1. General scheme for a one-pot conjugate addition protocol. Reaction overview with representative substrates. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59775/59775fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/59775/59775fig2v3.jpg" /> 
Figure 2. 1H NMR of 21. Spectrum obtained in CDCl3 at 400 MHz. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59775/59775fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/59775/59775fig3v3.jpg" /> 
Figure 3. 13C{1H} NMR of 21. 1H-decoupled spectrum obtained in CDCl3 at 101 MHz. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59775/59775fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/59775/59775fig4v2.jpg" /> 
Figure 4. Representative reaction scope for the one-pot conjugate addition of functionalized monoorganozincs. Yields indicate isolated analytically pure products conducted on 1.00 mmol scale of unsaturated ketone. Product 21 was isolated on 5.00 mmol scale of unsaturated ketone. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/59775/59775fig4large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td colspan="5"><img alt="Equation" src="/files/ftp_upload/59775/59775eq1v2.jpg" /></td>
		</tr>
		<tr>
			<td>entrya</td>
			<td>36 (equiv)</td>
			<td>CuBr&#8226;DMS (mol %)</td>
			<td>TMSCl (equiv)</td>
			<td>yield 21 (%)b</td>
		</tr>
		<tr>
			<td>1</td>
			<td>2</td>
			<td>20</td>
			<td>2.4</td>
			<td>90</td>
		</tr>
		<tr>
			<td>2</td>
			<td>2</td>
			<td>10</td>
			<td>2.4</td>
			<td>72</td>
		</tr>
		<tr>
			<td>3</td>
			<td>2</td>
			<td>0</td>
			<td>2.4</td>
			<td>0c</td>
		</tr>
		<tr>
			<td>4</td>
			<td>1.2</td>
			<td>20</td>
			<td>2.4</td>
			<td>72c</td>
		</tr>
		<tr>
			<td>5</td>
			<td>2</td>
			<td>20</td>
			<td>1.2</td>
			<td>73c</td>
		</tr>
		<tr>
			<td>6</td>
			<td>2</td>
			<td>20</td>
			<td>0</td>
			<td>0</td>
		</tr>
		<tr>
			<td>7</td>
			<td>2</td>
			<td>20</td>
			<td>2.4</td>
			<td>0 (74)d</td>
		</tr>
		<tr>
			<td colspan="5">a 1.00 mmol 13 according to standard protocol. b Isolated yields. c Incomplete conversion of 13. d Yield in parenthesis of 37, obtained from a NaHCO3 workup that omitted AcOH and HCl.</td>
		</tr>
	</tbody>
</table>
Table 1. Parameter optimization of the one-pot conjugate addition. A survey of reagent equivalence and reaction outcome.

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 ...

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

Nanyang Technological University

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Chemistry

9.2K Views.  California Institute of Technology. Ons protocol beschrijft een handige one-pot voorbereiding en koper-gemedieerde conjugaat toevoeging van gefunctionaliseerde monoorganozinc bromides aan cyclische alfa-beta-onverzadigde carbonyls voor de synthese van kwarternale centra in hoge opbrengst. Een belangrijk voordeel van deze methode omvat het gebruik van dimethylacetamide om organozincvorming van wijd toegankelijke gefunctionaliseerde organobromides te vergemakkelijken. Om te beginnen, voeg zink, stof, DMA, en jodium aan een vlam g...

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

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

Metal-free Synthesis of Ynones from Acyl Chlorides and Potassium Alkynyltrifluoroborate Salts

Ynones are a valuable functional group and building block in organic synthesis. Ynones serve as a precursor to many important organic functional groups and scaffolds. Traditional methods for the preparation of ynones are associated with drawbacks including harsh conditions, multiple purification steps, and the presence of unwanted byproducts. An alternative method for the straightforward preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts is described herein. The adoption of organotrifluoroborate salts as an alternative to organometallic reagents for the formation of new carbon-carbon bonds has a number of advantages. Potassium organotrifluoroborate salts are shelf stable, have good functional group tolerance, low toxicity, and a wide variety are straightforward to prepare. The title reaction proceeds rapidly at ambient temperature in the presence of a Lewis acid without the exclusion of air and moisture. Fair to excellent yields may be obtained via reaction of various aryl and alkyl acid chlorides with alkynyltrifluoroborate salts in the presence of boron trichloride.

The goal of this manuscript is to demonstrate a straightforward method for the preparation of ynones from acyl chloride and potassium alkynyltrifluoroborate salt starting materials. The one-pot reaction proceeds rapidly in the presence of boron trichloride without exclusion of air and moisture.

Ynones are a valuable functional group and building block in organic synthesis. Ynones serve as a precursor to many important organic functional groups ...

Preparation of a Corannulene-functionalized Hexahelicene by Copper(I)-catalyzed Alkyne-azide Cycloaddition of Nonplanar Polyaromatic Units

The main purpose of this video is to show 6 reaction steps of a convergent synthesis and prepare a complex molecule containing up to three nonplanar polyaromatic units, which are two corannulene moieties and a racemic hexahelicene linking them. The compound described in this work is a good host for fullerenes. Several common organic reactions, such as free-radical reactions, C-C coupling or click chemistry, are employed demonstrating the versatility of functionalization that this compound can accept. All of these reactions work for planar aromatic molecules. With subtle modifications, it is possible to achieve similar results for nonplanar polyaromatic compounds.

Preparation of a Corannulene-functionalized Hexahelicene by CopperI-catalyzed Alkyne-azide Cycloaddition of Nonplanar Polyaromatic Units

Here, we present a protocol to synthesize a complex organic compound comprised of three nonplanar polyaromatic units, assembled easily with reasonable yields.

The main purpose of this video is to show 6 reaction steps of a convergent synthesis and prepare a complex molecule containing up to three nonplanar ...

Chemoselective Preparation of 1-Iodoalkynes, 1,2-Diiodoalkenes, and 1,1,2-Triiodoalkenes Based on the Oxidative Iodination of Terminal Alkynes

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and 1-methyl-4-(1,2,2-triiodovinyl)benzene as representative examples for the practical chemoselective preparation of 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes from the chemoselective iodination of terminal alkynes mediated by hypervalent-iodine reagents. The chemoselectivity was confirmed by using p-tolylethyne as a model substrate to screen a variety of iodine sources and/or the hypervalent-iodine reagents. A combination of tetrabutylammonium iodide (TBAI) and (diacetoxyiodo)benzene (PIDA) selectively generates 1-iodoalkynes, while a combination of KI and PIDA generates 1,2-diiodoalkenes. A one-pot synthesis based on both TBAI-PIDA and KI-PIDA yields the corresponding 1,1,2-triiodoalkenes. These protocols were subsequently applied to the synthesis of synthetically important aromatic and aliphatic 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes, which were obtained in good yield with excellent chemoselectivity.

Herein, detailed protocols for the oxidative iodination of terminal alkynes using hypervalent-iodine reagents are presented, which chemoselectively afford 1-iodoalkynes, 1,2-diiodoalkenes, and 1,1,2-triiodoalkenes.

We present the chemoselective synthesis of 1-(iodoethynyl)-4-methylbenzene, 1-(1,2-diiodovinyl)-4-methylbenzene, and ...

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of &#945;-Imino &#947;-Lactones and Alkylidene Pyrazolones

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. Recently, we have developed an efficient organocatalytic strategy, which provides facile access to a variety of enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons. In this paper, we demonstrate a detailed protocol for the asymmetric synthesis of drug-like bispirocyclic compounds with two spirocyclic carbon centers via an organocatyltic 1,3-dipolar cycloaddition reaction. Spirocyclization synthons &#945;-imino &#947;-lactones and alkylidene pyrazolones are prepared first, which are then subjected to a cycloaddition reaction in the presence of a bifunctional squaramide organocatalyst to afford the desired bispirocycles in high yields and excellent stereoselectivities. Chiral high-performance liquid chromatography (HPLC) is carried out to determine the enantiomeric purity of the products, and the d.r. value is examined by proton nuclear magnetic resonance (1H NMR). The absolute configuration of the product is assigned according to an X-ray crystallographic analysis. This synthetic strategy allows scientists to prepare a diversity of bispirocyclic scaffolds in high yields and excellent diastereo- and enantioselectivities.

Enantiomerically enriched bispiro[&#947;-butyrolactone-pyrrolidin-4,4&#39;-pyrazolone] skeletons are asymmetrically synthesized through a simple organocatalytic 1,3-dipolar cycloaddition reaction.

Bispirocyclic scaffolds are one of the important structural subunits in many natural products that exhibit diverse and attractive biological activities. ...

Isolating Free Carbenes, their Mixed Dimers and Organic Radicals

Protocols for the isolation of the commonly employed cyclic (alkyl)(amino) carbene (CAAC) and N-heterocyclic carbene (NHC) are reported. Furthermore, the synthesis of their mixed CAAC&#8211;NHC &#8220;Wanzlick&#8221; dimer and the synthesis of the related stable organic &#8220;olefin&#8221; radical are presented. The main goal of this manuscript is to give a detailed and general protocol for the synthetic chemist of any skill level on how to prepare free heterocyclic carbenes by deprotonation using filter cannulas. Due to the air-sensitivity of the synthesized compounds, all experiments are performed under inert atmosphere using either Schlenk technique or a dinitrogen filled glovebox. Controlling Wanzlick&#8217;s equilibrium (i.e., the dimerization of free carbenes), is a crucial requirement for the application of free carbenes in coordination chemistry or organic synthesis. Thus, we elaborate on the specific electronic and steric requirements favoring the formation of dimers, heterodimers, or monomers. We will show how proton catalysis allows for the formation of dimers, and how the electronic structure of carbenes and their dimers affects the reactivity with either moisture or air. The structural identity of the reported compounds is discussed based on their NMR spectra.

We present protocols for the isolation of stable heterocyclic carbenes. The synthesis of a cyclic (alkyl)(amino) carbene (CAAC) and an N-heterocyclic carbene (NHC) is demonstrated using filter cannulas and Schlenk technique. We furthermore present the synthesis of the related oxygen-sensitive, electron-rich mixed &#8220;Wanzlick dimer&#8221; and the reduced stable organic radical.

Protocols for the isolation of the commonly employed cyclic (alkyl)(amino) carbene (CAAC) and N-heterocyclic carbene (NHC) are reported. Furthermore, the ...

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products and notably to generate chiral carbon centers. The crucial first step consists in the selective double hydroboration of CO2 catalyzed by an iron hydride complex. The product obtained with this 4 e- reduction is a rare bis(boryl)acetal, compound 1, which is subjected in situ to three different reactions in a second step. The first reaction concerns a condensation reaction with (diisopropyl)phenylamine affording the corresponding imine 2. In the second and third reaction, intermediate 1 reacts with triazol-5-ylidene (Enders&#39; carbene) to afford compounds 3 or 4, depending on the reaction conditions. In both compounds, C-C bonds are formed, and chiral centers are generated from CO2 as the only source of carbon. Compound 4 exhibits two chiral centers obtained in a diastereoselective manner in a formose-type mechanism. We proved that the remaining boryl fragment plays a key role in this unprecedented stereocontrol. The interest of the method stands on the reactive and versatile nature of 1, giving rise to various complex molecules from a single intermediate. The complexity of a two-step method is compensated by the overall short reaction time (2 h for the larger reaction time), and mild reaction conditions (25 &#176;C to 80 &#176;C and 1 to 3 atm of CO2).

Versatile CO2 Transformations into Complex Products: A One-pot Two-step Strategy

CO2 transformations are conducted in a one-pot two-step procedure for the synthesis of complex molecules. The selective 4 e- reduction of CO2 with a hydroborane reductant affords a reactive and versatile bis(boryl)acetal intermediate which is subsequently involved in condensation reaction or carbene-mediated C-C coupling generation.

CO2 transformations using a one-pot two-step method are presented herein. The purpose of the method is to give access to a variety of value-added products ...

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite classical and recent approaches toward functionalized benzenes, in water metal-free methods remains a challenge and represents an opportunity to expand even more the set of tools used to synthesize polysubstituted benzene compounds. This protocol describes an operationally simple experimental setup to explore the benzannulation of &#945;,&#946;-unsaturated compounds and alkynes to afford unprecedented functionalized benzene rings in high yields. Ammonium persulfate is the reagent of choice and brings notable advantages as stability and easy handling. Moreover, the use of water as a solvent and the absence of metals impart more sustainability to the method. A modified workup procedure that avoids the use of drying agents also adds convenience to the protocol. The purification of the products is performed using only a plug of silica. The substrate scope is currently limited to terminal alkynes and &#945;,&#946;-unsaturated aliphatic compounds.

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of &#945;,&#946;-Unsaturated Compounds and Alkynes

A persulfate-promoted metal-free benzannulation of &#945;,&#946;-unsaturated compounds and alkynes in water toward the synthesis of unprecedented polyfunctionalized benzenes is reported.

Benzannulation reactions represent an effective protocol to transform acyclic building blocks into structurally varied benzene skeletons. Despite ...

Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used to manage and treat pain and inflammation. In 2016, a new class of boron functionalized NSAIDs (bora-NSAIDs) was synthesized under mild conditions via the copper-catalyzed regioselective boracarboxylation of vinyl arenes using carbon dioxide (CO2 balloon) and a diboron reductant at room temperature. This original method was performed primarily in a glovebox or with a vacuum gas manifold (Schlenk line) under rigorous air-free and moisture-free conditions, which often led to irreproducible reaction outcomes due to trace impurities. The present protocol describes a simpler and more convenient benchtop method for synthesizing a representative bora-NSAID, bora-ibuprofen. A Suzuki-Miyaura cross-coupling reaction between 1-bromo-4-isobutylbenzene and vinylboronic acid pinacol ester produces 4-isobutylstyrene. The styrene is subsequently boracarboxylated regioselectively to provide bora-ibuprofen, an &#945;-aryl-&#946;-boryl-propionic acid, with good yield on a multi-gram scale. This procedure allows for the broader utilization of copper-catalyzed boracarboxylation in synthetic laboratories, enabling further research on bora-NSAIDs and other unique boron-functionalized drug-like molecules.

The present protocol describes a detailed benchtop catalytic method that yields a unique borylated derivative of ibuprofen.&#160;

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drugs used to manage and treat pain and inflammation. In 2016, a new class of ...

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

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