We would like to thank the National Science Foundation CAREER and MRI programs (CHE-1752986 and CHE-1228336), the West Virginia University Honors EXCEL Thesis Program (ASS &#38; ACR), the West Virginia University Research Apprenticeship (RAP) and Summer Undergraduate Research Experience (SURE) Programs (ACR), and the Brodie family (Don and Linda Brodie Resource Fund for Innovation) for their generous support of this research.

1. Synthesis of 4-isobutylstyrene through Suzuki cross-coupling of 1-bromo-4-isobutylbenzene with vinylboronic acid pinacol ester
<ol>
	<li>Add 144 mg of palladium(0) tetrakistriphenylphosphine (5 mol%, see the Table of Materials), 1.04 g of anhydrous potassium carbonate (2 eq), and a magnetic stir bar (0.5 in x 0.125 in) to a 40 mL scintillation vial, and then seal with a pressure relief cap. Completely encapsulate the vial seal with electrical tape.
	<ol>
		<li>Purge the reaction mixture with argon for 2 min. After the 2 min, add 1.07 g of 1-bromo-4-isobutylbenzene (1 eq, see Table of Materials), then add 13 mL of anhydrous tetrahydrofuran (THF) obtained from a solvent purification system (or still pot) with continuous argon flow, and then commence magnetic stirring. 
		NOTE: Argon gas can be replaced with dry nitrogen gas.</li>
		<li>Add 1.5 mL of argon-sparged deionized water to the solution, followed by 0.72 mL of vinylboronic acid pinacol ester (1.5 eq, see Table of Materials), and then purge the reaction mixture with argon for an additional 5 min.</li>
		<li>Once the argon purging is over, heat the reaction mixture at 85 &#176;C for 24 h on a stirring hot plate (see the Table of Materials).</li>
		<li>After 24 h, remove a small aliquot from the reaction mixture, dilute it with 2 mL of dichloromethane, and then perform thin layer chromatography (TLC, UV visualization) using hexane to ensure reaction completion (Rf = 0.9 reactant, Rf = 0.91 product).</li>
	</ol>
	</li>
	<li>Upon the confirmation of 1-bromo-4-isobutylbenzene consumption, add the reaction mixture to a 125 mL separatory funnel, and then add 30 mL of deionized water.
	<ol>
		<li>Extract 3x with 5 mL of dichloromethane, add the organic extracts to a 125 mL Erlenmeyer flask (see Table of Materials), and then discard the aqueous layer.</li>
		<li>Transfer the organic extracts into a 125 mL separatory funnel, wash with 30 mL of brine (an aqueous saturated sodium chloride solution), and discard the brine.</li>
		<li>Transfer the organic layer to a 125 mL Erlenmeyer flask, then add 5 g of sodium sulfate, and swirl the flask for at least 20 s.</li>
		<li>Using a Buchner funnel (see Table of Materials), vacuum filter the solution into a 125 mL filter flask.</li>
		<li>Transfer the organic layer to a 100 mL round-bottom flask, and then concentrate the reaction in a vacuum&#160;for 15-30 min (depending on the vacuum strength) to provide a pale yellow viscous oil.</li>
	</ol>
	</li>
	<li>Subject the crude reaction mixture to column chromatography using 50 g of SilicaFlash P60 silica gel (see the Table of Materials) and pure hexane as the eluent to obtain pure 4-isobutylstyrene (1) (Figure 2). 
	NOTE: For the present study, the yield was 89% (average of three reactions). The 4-isobutylstyrene is subjected to polymerization at room temperature under light, so once isolated, the product must be stored in the dark at or below &#8722;20 &#176;C until needed. If necessary, a small amount of butylated hydroxytoluene (BHT) can be added to inhibit polymerization. BHT does not impact the efficiency of copper-catalyzed boracarboxylation.</li>
</ol>
2. Large-scale synthesis of&#160;&#160;bora-ibuprofen in a glovebox
NOTE: This reaction was prepared inside a nitrogen-filled glovebox (see the Table of Materials). All the chemicals were dried or purified before moving into the box. The 4-isobutylstyrene was freeze-pump-thawed prior to use. All the vials and glassware were dried and heated in an oven (180 &#176;C) for at least 24 h prior to use. The copper precatalyst (ICyCuCl) was prepared according to a previously published report29.
<ol>
	<li>Add 160 mg of ICyCuCl (5 mol%), 131 mg of triphenylphosphine (5 mol%), 1.92 g of sodium tert-butoxide (2 eq), 20 mL of anhydrous, degassed THF, and a 0.5 in x 0.125 in magnetic stir bar to a 20 mL scintillation vial, then seal with an air-tight septum, and stir the resulting solution for 20 min.
	<ol>
		<li>After 20 min, transfer the catalyst solution to a 60 mL syringe, and plug the needle into a septum.</li>
		<li>Add 2.79 g of bis(pinacolato)diboron (1.1 eq), 1.87 mL of 4-isobutylstyrene (1 eq), 140 mL of THF, and a 2 in x 0.3125 in magnetic stir bar to a 500 mL round-bottom flask, seal with a septum, and then tape around the septum until the seal is encapsulated.</li>
	</ol>
	</li>
	<li>Remove the 500 mL round-bottom flask containing the styrene solution and the 60 mL syringe containing the catalyst solution from the glovebox, and move to a fume hood. 
	NOTE: After preparation, the 500 mL round-bottom flask and catalyst solution syringe must be removed immediately from the glovebox. The styrene substrate is subjected to polymerization in THF, and the catalyst solution decomposes upon standing for a long period of time or upon exposure to air.
	<ol>
		<li>Begin purging the 500 mL round-bottom flask with carbon dioxide (bone dry) (see the&#160;Table of Materials). After 5 minutes, add the catalyst solution over 30 s, purge for an additional 10 minutes, and then stir the reaction at ambient temperature for 3 h.</li>
		<li>After 3 h, again purge the round-bottom flask with carbon dioxide (bone dry) (see the Table of Materials) for 15 min, and then stir at ambient temperature for 33 h.</li>
	</ol>
	</li>
	<li>Upon reaction completion, concentrate the reaction mixture in a vacuum, and then acidify with 30 mL of aqueous HCl (1.0 M).
	<ol>
		<li>Add 50 mL of diethyl ether to the round-bottom flask containing the acidified reaction solution, swirl the solution for at least 10 s, transfer the solution to a 500 mL separatory funnel, and separate the organic and aqueous layers by adding the aqueous layer to a 1,000 mL Erlenmeyer flask.</li>
		<li>Extract the organic layer (8x) with 50 mL of saturated NaHCO3, and transfer the aqueous extracts to a 1,000 mL Erlenmeyer flask.</li>
		<li>Acidify the combined aqueous layers in the 1,000 mL Erlenmeyer flask with 12 M HCl (to pH &#8804; 1.0 by litmus paper), and transfer the solution to a clean 1,000 mL separatory funnel.</li>
		<li>Extract the aqueous solution (8x) with 50 mL of dichloromethane, and transfer the organic extracts to a clean 1,000 mL Erlenmeyer flask.</li>
		<li>Add 50 g of sodium sulfate to the organic extraction solution, and swirl the flask for at least 20 s.</li>
		<li>Filter the organic extraction solution through a Buchner funnel, and collect it in a clean 1,000 mL filtration flask.</li>
		<li>Concentrate the reaction in a vacuum&#160;for 15-30 min (depending on the vacuum strength) to provide a pale yellow viscous oil.</li>
	</ol>
	</li>
	<li>Dissolve the residue in 10 mL of HPLC-grade heptane, and then store it in a freezer (&#8722;20 &#176;C) overnight to produce pure recrystallized bora-Ibuprofen (Figure 1). 
	&#8203;NOTE: In the present study, the bora-ibuprofen yield was 62% (average of two reactions).</li>
</ol>
3. Benchtop large-scale synthesis of&#160;&#160;bora-ibuprofen
NOTE: This reaction procedure was carried out without using a nitrogen-filled glovebox. All the chemicals were used as received or synthesized without further purification (drying, distilling, etc.). All the vials and glassware were dried and heated in an oven (180 &#176;C) for at least 24 h prior to use and cooled under argon to room temperature immediately before the reaction setup.
<ol>
	<li>Add 334 mg of ICyH&#8226;Cl (13 mol%), 2.92 g of sodium tert-butoxide (3 eq), and a 0.5 in x 0.125 in magnetic stir bar to a 20 mL scintillation vial, then seal with an air-tight septum, and immediately purge with argon for 5 min.
	<ol>
		<li>Add 20 mL of anhydrous, degassed THF via a syringe to the 20 mL scintillation vial containing the ligand and base mixture, purge the resulting solution for 5 min with argon, and then stir for an additional 30 min.</li>
		<li>Add 119 mg of CuCl (12 mol%) and a 0.5 in x 0.125 in magnetic stir bar to a 20 mL scintillation vial, then seal with an air-tight septum, and immediately purge with argon for 5 min. After stirring the ligand solution (from step 3.1.1) for 30 min, add it to the CuCl scintillation vial under a positive argon flow, and then stir the resulting solution for 1 h. 
		NOTE: When weighing out the CuCl, take care to place it directly in the center of the bottom of the scintillation vial, as it tends to get stuck around the inside corner edges of the vial, resulting in poor dissolution in the ligand solution.</li>
	</ol>
	</li>
	<li>Add 5.08 g of bis(pinacolato)diboron (2 eq) and a 2 x 0.3125 in. magnetic stir bar to a 500 mL round-bottom flask and seal with a septum, and then encapsulate the septum seal with black electrical tape. Once sealed, add 140 mL of THF and 1.78 mL of 4-isobutylstyrene (1 eq) to the flask, and then purge with argon for 5 min.
	<ol>
		<li>Purge the 500 mL round-bottom flask with dry carbon dioxide immediately following the argon purge. Then, add the catalyst solution (from step 3.1.2) for 30 s, continue purging with dry carbon dioxide for 15 min, and then stir the reaction at ambient temperature for 16 h.</li>
	</ol>
	</li>
	<li>Concentrate the reaction mixture for 15-30 min in a vacuum upon reaction completion, and then acidify with 30 mL of aqueous HCl (1.0 M).
	<ol>
		<li>Add 50 mL of diethyl ether to the round-bottom flask containing the acidified reaction solution, swirl the solution for at least 10 s, transfer the solution to a 500 mL separatory funnel, separate organic and aqueous layers, and add the aqueous layer to a 1,000 mL Erlenmeyer flask.</li>
		<li>Extract the organic layer (8x) with 50 mL of saturated NaHCO3, and transfer the aqueous extracts to a 1,000 mL Erlenmeyer flask.</li>
		<li>Acidify the combined aqueous layers in the 1,000 mL of Erlenmeyer flask with 12 M HCl (to pH &#8804; 1.0 by litmus paper), and transfer the solution to a clean 1,000 mL separatory funnel.</li>
		<li>Extract the aqueous solution (8x) with 50 mL dichloromethane, and transfer the organic extracts to a clean 1,000 mL Erlenmeyer flask.</li>
		<li>Add 50 g of sodium sulfate to the organic extraction solution, and swirl the flask for at least 20 s.</li>
		<li>Filter the organic extraction solution through a Buchner funnel, and collect it in a clean 1,000 mL filtration flask. Transfer the filtrate to a round-bottom flask.</li>
		<li>Concentrate the reaction in a vacuum&#160;for 15-30 min (depending on the vacuum strength) to provide a pale yellow viscous oil.</li>
	</ol>
	</li>
	<li>Dissolve the residue in 10 mL of HPLC-grade heptane, and then store it in a freezer (&#8722;20 &#176;C) overnight to produce pure recrystallized bora-ibuprofen (Figure 1). 
	NOTE: For the present study, the yield of bora-ibuprofen was 59%.</li>
</ol>

<ol>
	<li>Bose, S. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=First-row+d-block+element-catalyzed+carbon-boron+bond+formation+and+related+processes.">First-row d-block element-catalyzed carbon-boron bond formation and related processes.</a> Chemical Reviews. 121 (21), 13238-13341 (2021).</li><li>Hemming, D., Fritzemeier, R., Westcott, S. A., Santos, W. L., Steel, P. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper-boryl+mediated+organic+synthesis.">Copper-boryl mediated organic synthesis.</a> Chemical Society Reviews. 47 (19), 7477-7494 (2018).</li><li>Taniguchi, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Boryl+radical+addition+to+multiple+bonds+in+organic+synthesis.">Boryl radical addition to multiple bonds in organic synthesis.</a> European Journal of Organic Chemistry. 2019 (37), 6308-6319 (2019).</li><li>Budiman, Y. P., Westcott, S. A., Radius, U., Marder, T. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fluorinated+aryl+boronates+as+building+blocks+in+organic+synthesis.">Fluorinated aryl boronates as building blocks in organic synthesis.</a> Advanced Synthesis &amp; Catalysis. 363 (9), 2224-2255 (2021).</li><li>Wang, M., Shi, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Methodologies+and+strategies+for+selective+borylation+of+C-Het+and+C-C+bonds.">Methodologies and strategies for selective borylation of C-Het and C-C bonds.</a> Chemical Reviews. 120 (15), 7348-7398 (2020).</li><li>Tian, Y. -. M., Guo, X. -. N., Braunschweig, H., Radius, U., Marder, T. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Photoinduced+borylation+for+the+synthesis+of+organoboron+compounds:+Focus+review.">Photoinduced borylation for the synthesis of organoboron compounds: Focus review.</a> Chemical Reviews. 121 (7), 3561-3597 (2021).</li><li>Brown, H. C., Rathke, M. W., RogiC&#180;, M. M., De Lue, N. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Organoboranes+for+synthesis.+9.+Rapid+reaction+of+organoboranes+with+iodine+under+the+influence+of+base.+A+convenient+procedure+for+the+conversion+of+alkenes+into+iodides+via+hydroboration.">Organoboranes for synthesis. 9. Rapid reaction of organoboranes with iodine under the influence of base. A convenient procedure for the conversion of alkenes into iodides via hydroboration.</a> Tetrahedron. 44 (10), 2751-2762 (1988).</li><li>Shegavi, M. L., Bose, S. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Recent+advances+in+the+catalytic+hydroboration+of+carbonyl+compounds.">Recent advances in the catalytic hydroboration of carbonyl compounds.</a> Catalysis Science and Technology. 9 (13), 3307-3336 (2019).</li><li>Clay, J. M., Vedejs, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hydroboration+with+pyridine+borane+at+room+temperature.">Hydroboration with pyridine borane at room temperature.</a> Journal of the American Chemical Society. 127 (16), 5766-5767 (2005).</li><li>Mao, L., Bose, S. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hydroboration+of+enynes+and+mechanistic+insights.">Hydroboration of enynes and mechanistic insights.</a> Advanced Synthesis &amp; Catalysis. 362 (20), 4174-4188 (2020).</li><li>Pattison, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fluorination+of+organoboron+compounds.">Fluorination of organoboron compounds.</a> Organic &amp; Biomolecular Chemistry. 17 (23), 5651-5660 (2019).</li><li>Zhu, C., Falck, J. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transition+metal-free+ipso-functionalization+of+arylboronic+acids+and+derivatives.">Transition metal-free ipso-functionalization of arylboronic acids and derivatives.</a> Advanced Synthesis &amp; Catalysis. 356 (11-12), 2395-2410 (2014).</li><li>Chen, J., Li, J., Dong, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+review+on+the+latest+progress+of+Chan-Lam+coupling+reaction.">A review on the latest progress of Chan-Lam coupling reaction.</a> Advanced Synthesis &amp; Catalysis. 362 (16), 3311-3331 (2020).</li><li>Rucker, R. P., Whittaker, A. M., Dang, H., Lalic, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+tertiary+alkyl+amines+from+terminal+alkenes:+Copper-catalyzed+amination+of+alkyl+boranes.">Synthesis of tertiary alkyl amines from terminal alkenes: Copper-catalyzed amination of alkyl boranes.</a> Journal of the American Chemical Society. 134 (15), 6571-6574 (2012).</li><li>Miyaura, N., Suzuki, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Palladium-catalyzed+cross-coupling+reactions+of+organoboron+compounds.">Palladium-catalyzed cross-coupling reactions of organoboron compounds.</a> Chemical Reviews. 95 (7), 2457-2483 (1995).</li><li>Lennox, A. J. J., Lloyd-Jones, G. C. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selection+of+boron+reagents+for+Suzuki-Miyaura+coupling.">Selection of boron reagents for Suzuki-Miyaura coupling.</a> Chemical Society Reviews. 43 (1), 412-443 (2014).</li><li>Osakada, K., Nishihara, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Transmetalation+of+boronic+acids+and+their+derivatives:+mechanistic+elucidation+and+relevance+to+catalysis.">Transmetalation of boronic acids and their derivatives: mechanistic elucidation and relevance to catalysis.</a> Dalton Transactions. 51 (3), 777-796 (2022).</li><li>Sharma, S., Das, J., Braje, W. M., Dash, A. K., Handa, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+glimpse+into+green+chemistry+practices+in+the+pharmaceutical+industry.">A glimpse into green chemistry practices in the pharmaceutical industry.</a> ChemSusChem. 13 (11), 2859-2875 (2020).</li><li>Bhaskaran, S., Padusha, M. S. A., Sajith, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Application+of+palladium+based+precatalytic+systems+in+the+Suzuki-Miyaura+cross-coupling+reactions+of+chloro-heterocycles.">Application of palladium based precatalytic systems in the Suzuki-Miyaura cross-coupling reactions of chloro-heterocycles.</a> ChemistrySelect. 5 (29), 9005-9016 (2020).</li><li>Fujihara, T., Tani, Y., Semba, K., Terao, J., Tsuji, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper-catalyzed+silacarboxylation+of+internal+alkynes+by+employing+carbon+dioxide+and+silylboranes.">Copper-catalyzed silacarboxylation of internal alkynes by employing carbon dioxide and silylboranes.</a> Angewandte Chemie International Edition. 51 (46), 11487-11490 (2012).</li><li>Tani, Y., Fujihara, T., Terao, J., Tsuji, Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Copper-catalyzed+regiodivergent+silacarboxylation+of+allenes+with+carbon+dioxide+and+a+silylborane.">Copper-catalyzed regiodivergent silacarboxylation of allenes with carbon dioxide and a silylborane.</a> Journal of the American Chemical Society. 136 (51), 17706-17709 (2014).</li><li>Zhang, L., Cheng, J., Carry, B., Hou, Z. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Catalytic+boracarboxylation+of+alkynes+with+diborane+and+carbon+dioxide+by+an+N-heterocyclic+carbene+copper+catalyst.">Catalytic boracarboxylation of alkynes with diborane and carbon dioxide by an N-heterocyclic carbene copper catalyst.</a> Journal of the American Chemical Society. 134 (35), 14314-14317 (2012).</li><li>Schwarz, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Atypical Elements in Drug Design. , (2016).</li><li>Laitar, D. S., Tsui, E. Y., Sadighi, J. P. <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)+&#946;-boroalkyls+from+alkene+insertion:+Isolation+and+rearrangement.">Copper(I) &#946;-boroalkyls from alkene insertion: Isolation and rearrangement.</a> Organometallics. 25 (10), 2405-2408 (2006).</li><li>Mankad, N. P., Laitar, D. S., Sadighi, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis,+structure,+and+alkyne+reactivity+of+a+dimeric+(carbene)copper(I)+hydride.">Synthesis, structure, and alkyne reactivity of a dimeric (carbene)copper(I) hydride.</a> Organometallics. 23 (14), 3369-3371 (2004).</li><li>Butcher, T. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regioselective+copper-catalyzed+boracarboxylation+of+vinyl+arenes.">Regioselective copper-catalyzed boracarboxylation of vinyl arenes.</a> Organic Letters. 18 (24), 6428-6431 (2016).</li><li>Perrone, T. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Beneficial+effect+of+a+secondary+ligand+on+the+catalytic+difunctionalization+of+vinyl+arenes+with+boron+and+CO2.">Beneficial effect of a secondary ligand on the catalytic difunctionalization of vinyl arenes with boron and CO2.</a> ChemCatChem. 11 (23), 5814-5820 (2019).</li><li>Knowlden, S. W., Popp, B. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regioselective+boracarboxylation+of+&#945;-substituted+vinyl+arenes.">Regioselective boracarboxylation of &#945;-substituted vinyl arenes.</a> Organometallics. 41 (14), 1883-1891 (2022).</li><li>Santoro, O., Collado, A., Slawin, A. M. Z., Nolan, S. P., Cazin, C. S. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+general+synthetic+route+to+[Cu(X)(NHC)]+(NHC+=+N-heterocyclic+carbene,+X+=+Cl,+Br,+I)+complexes.">A general synthetic route to [Cu(X)(NHC)] (NHC = N-heterocyclic carbene, X = Cl, Br, I) complexes.</a> Chemical Communications. 49 (89), 10483 (2013).</li><li>Su, M., Huang, X., Lei, C., Jin, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nickel-catalyzed+reductive+cross-coupling+of+aryl+bromides+with+vinyl+acetate+in+dimethyl+isosorbide+as+a+sustainable+solvent.">Nickel-catalyzed reductive cross-coupling of aryl bromides with vinyl acetate in dimethyl isosorbide as a sustainable solvent.</a> Organic Letters. 24 (1), 354-358 (2022).</li><li>JoVE. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=JoVE+Science+Education+Database.+Organic+Chemistry.+Degassing+liquids+with+freeze-pump-thaw+cycling.">JoVE Science Education Database. Organic Chemistry. Degassing liquids with freeze-pump-thaw cycling.</a> Journal of Visual Experiments. , (2022).</li><li>Li, D., Ollevier, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mechanism+studies+of+oxidation+and+hydrolysis+of+Cu(I)-NHC+and+Ag-NHC+in+solution+under+air.">Mechanism studies of oxidation and hydrolysis of Cu(I)-NHC and Ag-NHC in solution under air.</a> Journal of Organometallic Chemistry. 906, 121025-121035 (2018).</li><li>Hern&#225;ndez-D&#237;az, S., Rodr&#237;guez, L. A. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Association+between+nonsteroidal+anti-inflammatory+drugs+and+upper+gastrointestinal+tract+bleeding/perforation:+An+overview+of+epidemiologic+studies+published+in+the+1990s.">Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: An overview of epidemiologic studies published in the 1990s.</a> Archives of Internal Medicine. 160 (14), 2093 (2000).</li><li>Wolfe, M. M., Singh, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gastrointestinal+toxicity+of+nonsteroidal+antiinflammatory+drugs.">Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs.</a> The New England Journal of Medicine. 340 (24), 1888-1899 (1999).</li><li>Singh, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gastrointestinal+tract+complications+of+non-steroidal+anti-inflammatory+drug+treatment+in+rheumatoid+arthritis.+A+prospective+observational+cohort+study.">Gastrointestinal tract complications of non-steroidal anti-inflammatory drug treatment in rheumatoid arthritis. A prospective observational cohort study.</a> Archives of Internal Medicine. 156 (14), 1530-1536 (1996).</li><li>Lichtenstein, D. R., Syngal, S., Wolfe, M. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Nonsteroidal+anti-inflammatory+drugs+and+the+gastrointestinal+tract+the+double-edged+sword.">Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract the double-edged sword.</a> Arthritis &amp; Rheumatism. 38 (1), 5-18 (1995).</li><li>Singh, G., Triadafilopoulos, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Epidemiology+of+NSAID+induced+gastrointestinal+complications.">Epidemiology of NSAID induced gastrointestinal complications.</a> The Journal of Rheumatology. 56, 18-24 (1999).</li></ol>

The authors declare no competing financial interests.

The 4-Isobutylstyrene (1) was obtained efficiently via a Suzuki cross-coupling reaction from inexpensive, commercially available 1-bromo-4-isobutylbenzene and vinylboronic acid pinacol ester. Compared to the Wittig approach, this reaction allows for the production of the desired styrene in a more environmentally friendly manner and with better atom economy. Reaction monitoring via TLC was crucial to ensure full conversion of the 1-bromo-4-isobutylbenzene substrate because reactions not ...

Organoboron compounds have been strategically employed in chemical synthesis for over 50 years1,2,3,4,5,6. Reactions such as hydroboration-oxidation7,8,9,10, halogenation11,12,&#160;amination13,14, and Suzuki-Miyaura cross-coupling15,16,17 have led to significant multidisciplinary innovations in chemistry and related disciplines. The Suzuki-Miyaura reactions, for example, account for 40% of all carbon-carbon bond-forming reactions in the pursuit of pharmaceutical drug candidates18. The Suzuki-Miyaura cross-coupling reaction produces vinyl arenes in one step from the halogenated arene precursor19.&#160;This greener catalytic strategy is valuable relative to traditional Wittig syntheses from aldehydes that have poor atom economy and produce a stoichiometric triphenylphosphine oxide byproduct.
It was predicted that a regioselective hetero(element)carboxylation of vinyl arenes would allow for direct access to novel hetero(element)-containing non-steroidal anti-inflammatory drugs (NSAIDs), utilizing CO2 directly in the synthesis. However, hetero(element)carboxylation reactions were exceedingly rare and were limited to alkynyl and allenyl substrates prior to 201620,21,22. The extension of the boracarboxylation reaction to vinyl arenes would provide boron-functionalized NSAIDs, and boron-based pharmaceutical candidates (Figure 1) have been gaining popularity, as indicated by recent decisions by the FDA to approve the chemotherapeutic bortezomib, the antifungal tavaborole, and the anti-inflammatory crisaborole. The Lewis acidity of boron is interesting from a drug design standpoint due to the capability to readily bind Lewis bases, such as diols, hydroxyl groups on carbohydrates, or nitrogen bases in RNA and DNA, since these Lewis bases play important roles in physiological and pathological processes23.
This catalytic approach to boracarboxylation relies upon borylcupration of the alkene by a Cu-boryl intermediate, followed by CO2 insertion into the resulting Cu-alkyl intermediate. Laitar et al. reported the borylcupration of styrene derivatives through the use of (NHC)Cu-boryl24, and the carboxylation of Cu-alkyl species has also been demonstrated25. In 2016, the Popp lab developed a new synthetic approach to achieve mild difunctionalization of vinyl arenes using an (NHC)Cu-boryl catalyst and only 1 atm of gaseous CO226. Using this method, the &#945;-aryl propionic acid pharmacophore is accessed in a single step, and a novel unexplored class of boron-modified NSAIDs can be prepared with excellent yield. In 2019, catalytic additives improved the catalyst efficiency and broadened the substrate scope, including the preparation of an additional two novel borylated NSAIDs27 (Figure 1).
Previous boracarboxylation reactions of alkenes could only be achieved under stringent air-free and moisture-free conditions with the use of an isolated N-heterocyclic-carbene-ligated copper(I) precatalyst (NHC-Cu; NHC = 1,3-bis(cyclohexyl)-1,3-dihydro-2H-imidazol-2-ylidene, ICy). A benchtop method wherein borylated ibuprofen can be synthesized using simple reagents would be more desirable for the synthetic community, prompting us to develop reaction conditions that allow for the boracarboxylation of vinyl arenes, particularly 4-isobutylstyrene, to proceed from the in situ generation of an NHC-Cu precatalyst and without the need of a glovebox. Recently, a boracarboxylation protocol was reported using imidazolium salts and copper(I)-chloride to generate in situ an active NHC-ligated copper(I) catalyst28. Using this method, &#945;-methyl styrene was boracarboxylated to give a 71% isolated yield of the desired product, albeit with the use of a glovebox. Inspired by this result, a modified procedure to boracarboxylate tert-butylstyrene without using a nitrogen-filled glovebox was devised. The desired boracarboxylated tert-butylstyrene product was produced with 90% yield on a 1.5 g scale. Gratifyingly, this method could be applied to 4-isobutylstyrene to produce a bora-ibuprofen NSAID derivative with moderate yield. The &#945;-aryl propionic acid pharmacophore is the core motif amongst NSAIDs; therefore, synthetic strategies that allow direct access to this motif are highly desirable chemical transformations. Herein, a synthetic pathway to access a unique bora-ibuprofen NSAID derivative from an abundant, inexpensive 1-bromo-4-isobutylbenzene starting material (~$2.50/1 g) with moderate yield in two steps, without the need for a glovebox, is presented.

<table><tbody><tr><td>125 mL filtration flask</td><td>ChemGlass</td><td></td><td></td></tr><tr><td>20 mL vial with pressure relief cap</td><td>ChemGlass</td><td></td><td></td></tr><tr><td>4-isobutylbromobenzene&amp;nbsp;</td><td>Matrix scientific</td><td>8824</td><td></td></tr><tr><td>Anhydrous potassium carbonate</td><td>Beantown chemicals</td><td>124060</td><td></td></tr><tr><td>Anhydrous sodium sulfate&amp;nbsp;</td><td>Oakwood</td><td>44702</td><td></td></tr><tr><td>Bis(pinacolato)diboron&amp;nbsp;</td><td>Boron Molecular chemicals</td><td>BM002</td><td></td></tr><tr><td>Buchner funnel with rubber adaptor</td><td>ChemGlass</td><td></td><td></td></tr><tr><td>Carbon dioxide gas (Bone dry)</td><td>Mateson</td><td></td><td>Tygon tubing connects cylinder regulator to needle used for reaction purging</td></tr><tr><td>COPPER(I) CHLORIDE, REAGENT GRADE, 97%</td><td>Aldrich</td><td>212946</td><td></td></tr><tr><td>Dichloromthane - high purity</td><td>Fisher</td><td>D37-20</td><td></td></tr><tr><td>Diethyl ether - high purity</td><td>Fisher</td><td>E138-20</td><td></td></tr><tr><td>Erlenmyer Flask, 125 mL</td><td>ChemGlass</td><td>CG-8496-125</td><td></td></tr><tr><td>filter paper</td><td>Fisher</td><td></td><td></td></tr><tr><td>Heptane</td><td>Fisher</td><td>H360-4</td><td></td></tr><tr><td>Hydrochloric acid</td><td>Fisher</td><td>AC124635001</td><td></td></tr><tr><td>IKA stirring hot plate</td><td>Fisher</td><td>3810001 RCT Basic MAG</td><td></td></tr><tr><td>Nitrogen filled glove box</td><td>MBRAUN</td><td></td><td></td></tr><tr><td>Palladium(0) tetrakistriphenylphosine&amp;nbsp;</td><td>Ark Pharm</td><td></td><td></td></tr><tr><td>SilicaFlash P60 silica gel</td><td>SiliCycle</td><td>R12030B</td><td></td></tr><tr><td>Sodium bicarbonate</td><td>Fisher</td><td>S233-3</td><td></td></tr><tr><td>Sodium tert-butoxide&amp;nbsp;</td><td>Fisher</td><td>A1994222</td><td></td></tr><tr><td>Tetrahydrofuran - high purity</td><td>Fisher</td><td>T425SK-4</td><td>Dried on a GlassContours Solvent Purification System</td></tr><tr><td>Triphenylphosphine</td><td>Sigma</td><td>T84409</td><td></td></tr><tr><td>Vacuum/gas manifold</td><td></td><td></td><td>Used for glovebox boracarboxyaltion reaction setup</td></tr><tr><td>Vinylboronic acid pinacol ester&amp;nbsp;</td><td>Oxchem</td><td></td><td></td></tr></tbody></table>

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 4-isobutylstyrene was characterized by 1H and 13C NMR spectroscopy. The bora-ibuprofen was characterized by 1H, 13C, and 11B NMR spectroscopy to confirm the product structure and assess the purity. The key data for these compounds are described in this section.
The spectral data are in good agreement with the structure of 4-isobutylstyrene (1) (Figure 2). The 1...

Watch this Scientific Journal Video about Synthesis of a Borylated Ibuprofen Derivative Through Suzuki Cross-Coupling and Alkene Boracarboxylation Reactions at JoVE.com

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

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 ...

synthesis-borylated-ibuprofen-derivative-through-suzuki-cross

Research

JoVE Journal

Chemistry

2.6K Views.  West Virginia University. The present protocol describes a detailed benchtop catalytic method that yields a unique borylated derivative of ibuprofen. 

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

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 ...

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. Detailed and generalized protocols are also presented for testing the catalytic activity of such complexes in arylation and Suzuki-Miyaura cross-coupling reactions. Representative results are shown for the catalytic activity of the four complexes in arylation and Suzuki-Miyaura type reactions. For each of the reactions investigated, at least one of the four complexes successfully catalyzed the reaction, qualifying them as promising candidates for catalysis of many carbon-carbon bond-forming reactions. The protocols presented are general enough to be adapted for the synthesis, purification and catalytic activity testing of new palladium N-heterocyclic carbene complexes.

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from benzimidazolium salts. The complexes were tested for catalytic activity in arylation and Suzuki-Miyaura reactions. For each reaction investigated, at least one of the four complexes successfully catalyzed the reaction.

Detailed and generalized protocols are presented for the synthesis and subsequent purification of four palladium N-heterocyclic carbene complexes from ...

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. ...

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.

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 ...

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 ...

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of ...

Palladium-Catalyzed Cross Coupling

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate the concept of a palladium-catalyzed cross coupling. The set-up of a typical Pd-catalyzed cross coupling reaction will be illustrated. Pd-catalyzed cross coupling reactions have had a profound effect on how synthetic chemists create molecules. These reactions have enabled chemists to construct bonds in new and more efficient ways. Such reactions have found widespread applications in the fine chemical and pharmaceutical industries. Pd-catalyzed cross coupling reactions add another tool to the chemist&#39;s toolbox for constructing carbon-carbon bonds, which are central to organic chemistry. The combination of the importance of making carbon-carbon bonds and the impact of Pd-catalyzed cross coupling have resulted in these reactions being the subject of the 2010 Nobel Prize in Chemistry. Ei-ichi Negishi, one of the recipients of the 2010 Nobel Prize in chemistry, explained in his Nobel lecture that one of his motivations for developing this chemistry was to develop &#34;widely applicable straightforward Lego-like methods for hooking up two different organic groups&#34;.

Palladium-Catalyzed Cross Coupling; Heck Coupling Reaction

Source: Vy M. Dong and Faben Cruz, Department of Chemistry, University of California, Irvine, CA
This experiment will demonstrate the concept of a ...

Education

JoVE Science Education

Organic Chemistry II

Hydroboration-Oxidation of Alkenes

In addition to the oxymercuration&#8211;demercuration method, which converts the alkenes to alcohols with Markovnikov orientation, a complementary hydroboration-oxidation method yields the anti-Markovnikov product. The hydroboration reaction, discovered in 1959 by H.C. Brown, involves the addition of a B&#8211;H bond of borane to an alkene giving an organoborane intermediate. The oxidation of this intermediate with basic hydrogen peroxide forms an alcohol.
<img alt="Figure1" src="/files/ftp_upload/11779/11779_PT_Figure_1.svg" style="text-align: center; height: 140px;" />
Borane as a reagent is very reactive, as the boron atom has only six electrons in its valence shell. The unoccupied 2p orbital of the boron is perpendicular to the plane, which is&#160;occupied by the boron and the three other hydrogens oriented at an angle of 120&#176;. Thus, borane is electrophilic with its structure resembling a carbocation without any charge.
<img alt="Figure2" src="/files/ftp_upload/11779/11779_PT_Figure_2.svg" style="text-align: center; height: 210px;" />
Due to high reactivity, two borane molecules dimerize such that two hydrogen atoms are partially bonded to two boron atoms with a total of two electrons. Hence, they are called three-center, two-electron bonds. Diborane co-exists in equilibrium with a small amount of borane.&#160;
<img alt="Figure3" src="/files/ftp_upload/11779/11779_PT_Figure_3.svg" style="text-align: center; height: 50px;" />
The electron-deficient borane easily accepts an electron pair from tetrahydrofuran to complete its octet forming a stable borane-ether complex. This is used as a reagent in hydroboration reactions under an inert atmosphere to avoid spontaneous ignition in the air.
<img alt="Figure4" src="/files/ftp_upload/11779/11779_PT_Figure_4.svg" style="text-align: center; height: 80px;" />
<h4>Hydroboration Mechanism</h4>
The mechanism starts with a borane attacking the &#960; bond at the less substituted and sterically less hindered site of an alkene forming a cyclic transition state. The overall result is a syn-addition of BH2 and hydrogen across the alkene double bond, producing an alkylborane. The reaction of a second alkene with the alkylborane yields a dialkylborane followed by the addition of a third alkene to produce a trialkylborane.
<img alt="Figure5" src="/files/ftp_upload/11779/11779_PT_Figure_5.svg" style="text-align: center; height: 200px;" />
<h4>Oxidation Mechanism</h4>
The oxidation begins with the deprotonation of hydrogen peroxide by a hydroxide ion forming a hydroperoxide. The hydroperoxide acts as a nucleophile and attacks the trialkylborane, resulting in an unstable intermediate. This is followed by the migration of an alkyl group from boron to the adjacent oxygen atom, releasing a hydroxide ion. This series of three steps is repeated to convert the remaining trialkylborane into a trialkoxyborane.
The boron atom of the trialkoxyborane is attacked by the nucleophilic hydroxide ion with the subsequent departure of the alkoxide ion neutralizing the formal charge on the boron atom. Finally, protonation of the alkoxide ion gives an alcohol as the final product.
<img alt="Figure6" src="/files/ftp_upload/11779/11779_PT_Figure_6.svg" style="text-align: center; height: 320px;" />

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

Summary

Explore More Videos

Chapters in this video

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

Palladium N-Heterocyclic Carbene Complexes: Synthesis from Benzimidazolium Salts and Catalytic Activity in Carbon-carbon Bond-forming Reactions

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

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones

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

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

Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions

Palladium-Catalyzed Cross Coupling

Hydroboration-Oxidation of Alkenes