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 proceeding to full conversion led to difficult flash chromatographic separation of the substrate and products.
The boracarboxylation of 4-isobutylstyrene with an NHC-copper(I) catalyst at ambient temperature using a pinacolato diboron reductant under an atmosphere of gaseous CO2 produced bora-ibuprofen (2) with high yield. It is important to note that the styrene must be rigorously freeze-pump-thawed31 to ensure no dioxygen remains in the solution, presumably due to copper(I)-aerobic decomposition32, which leads to diminished reactivity and unwanted side products such as formal hydroboration of the styrene. The catalyst must be added to the reaction mixture quickly due to the air-sensitive nature of the catalyst. A tell-tale sign that dioxygen has contaminated the reaction is the evolution of a sky-blue reaction color. Reactions that progress appropriately to high yield will appear cloudy white with a slight pink tint after the addition of the catalyst solution and then will turn to brown and, ultimately, light green after the reaction has been exposed to CO2 for 3 h or more. The boracarboxylation reaction can tolerate gentle heating up to 45 &#176;C, but higher temperatures lead to diminished yields27.
The reaction cannot be stored for any amount of time and must be immediately purified. The resulting end color of a successful boracarboxylation reaction is either brown or light green. Reactions not immediately purified will turn sky blue owing to copper oxidation with concomitant product decomposition. Product isolation is still possible, but diminished yields will occur. bora-Ibuprofen cannot be isolated by column chromatography of any type (e.g., silica gel, Florisil) and must be isolated following the acid-base workup protocol described above. Once isolated, bora-ibuprofen, as well as many other similar &#945;-aryl-&#946;-boryl proprionic acid derivatives studied thus far, is an air-stable white solid. Trace amounts of diboron reductant often remain after the first acid-base workup. A second acid-base workup followed by the second recrystallization in heptane often removes trace impurities to provide analytically pure products.
The benchtop boracarboxylation method is more convenient and easier to execute than the glovebox method while producing similar reaction outcomes. Nevertheless, there are some known limitations associated with the benchtop method. The reaction must be performed under moisture-free and air-free conditions. In order to further understand moisture sensitivity, a boracarboxylation reaction was performed using the benchtop method with &#34;wet&#34; THF (a high-purity 4 L bottle that was previously opened) for both the in situ catalyst preparation and the reaction steps. In this case, only a 2% NMR yield of the desired product was obtained. Next, a reaction was performed in which the catalyst solution was prepared using anhydrous THF (solvent system dried), while the remaining THF used in the reaction was &#34;wet&#34;. A modest increase to a 13% NMR yield of the boracarboxylated product was observed. It is clear that trace adventitious water impacts the reaction negatively, especially during pre-/active-catalyst formation. Using the benchtop protocol without an Ar purge (or N2 purge) of the reaction solution prior to the introduction of CO2 gas, an NMR yield of 46% (vs. 66% with Ar purge) was obtained. However, a second identical reaction setup provided an NMR yield of only 17%, suggesting that adventitious oxygen/air impacts the reaction in various irreproducible ways.
In the future, the Popp Group expects that bora-ibuprofen, and other boracarboxylated compounds will provide access to a host of other functionalized ibuprofen derivatives (Figure 9), thus allowing for their study as potential therapeutic agents for pain management33,34,35,36,37 or other pharmaceutical applications.

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 border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<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&#160;</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&#160;</td>
			<td>Oakwood</td>
			<td>44702</td>
			<td></td>
		</tr>
		<tr>
			<td>Bis(pinacolato)diboron&#160;</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&#160;</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&#160;</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&#160;</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 1H NMR spectrum obtained in CDCl3 (Figure 3) shows the characteristic AMX splitting pattern seen for monosubstituted styrene derivatives. These resonances are observed as a doublet at 5.17 (d, J = 10.9 Hz, 1H), a doublet at 5.69 (d, J = 17.6 Hz, 1H), and a doublet of doublets at 6.62-6.78 (dd, J = 10.9, 17.6 Hz, 1H). A second characteristic feature is the iso-butyl methine proton, appearing as a nonet at 2.37-2.52 (m, 2H) with corresponding methyl groups at 0.89 (d, J = 6.6 Hz, 6H)30. The nine resonances observed in the 13C NMR spectrum agree with literature values30 (Figure 4).
The synthesis of 4-isobutylstyrene via this protocol reliably produces the product with 89% yield (average of three reactions, 5 mmol scale); however, deviation from any of the key reaction conditions, such as the temperature and time, significantly impacts the efficiency of the reaction. The reaction must be heated at no less than 85 &#176;C. The reaction completion must be verified by TLC at or after 24 h.
The spectral data are in good agreement with the structure of the boracarboxylated product (2) (Figure 5). As with the previous substrate, the 1H NMR spectrum obtained in CDCl3 (Figure 6) shows an ABX splitting pattern, but this pattern occurs due to diastereotopic methylene protons arising from the newly generated benzylic stereogenic center. The AB resonances are observed as a doublet of doublets at 1.53 (dd, J = 16.0, 9.1 Hz, 1H) and 1.29 (dd, J = 16.0, 7.6 Hz, 1H), while the X resonance is observed at 3.82 (dd, J = 9.1, 7.6 Hz, 1H). The latter resonance is deshielded, which is consistent with a methine proton alpha to two sp2 carbons. Another set of significant resonances are at 1.12 (s, 6H) and 1.11 (s, 6H), corresponding to magnetically inequivalent methyl groups on the two sides of the pinacolato boron moiety26.
The 13C NMR spectrum of boracarboxylated product 2 (Figure 7) shows a very broad signal at 16 ppm, which is characteristic of a quadrupolar-broadened carbon bound to the boron. Another significant resonance is at 180.8 ppm, corresponding to the carbonyl carbon of the free carboxylic acid group.
The 11B NMR spectrum (Figure 8) shows a single broad resonance at 33.0&#160;ppm, which is characteristic of a trivalent boronic ester.
The synthesis of bora-ibuprofen via this protocol reliably produces the product with 62% yield (average of two reactions, 2.05 g isolated); however, this reaction is far more sensitive than the previous Suzuki cross-coupling reaction. Any deviation from the reported protocol will result in significantly diminished yields. Particular attention needs to be paid to the air-sensitive nature of this reaction. Using the benchtop protocol, the large-scale synthesis of bora-ibuprofen provide the desired product with a 59% yield (1.95 g isolated), comparable to the glovebox method.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/64571/64571fig01.jpg" /> 
Figure 1: Medicinal relevance of organoboron compounds. (A) The carboxylic acid group contains non-steroidal anti-inflammatory drugs. (B) FDA-approved boron-containing pharmaceuticals. (C) Boron-containing NSAID analogs (bora-NSAIDs). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig01large.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/64571/64571fig02.jpg" /> 
Figure 2: Synthesis of 4-isobutylstyrene (1) via the Suzuki cross-coupling reaction. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig02large.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/64571/64571fig03.jpg" /> 
Figure 3: 1H NMR spectrum of 4-isobutylstyrene (1). The 1H NMR spectrum was obtained in CDCl3. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig03large.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/64571/64571fig04.jpg" /> 
Figure 4: 13C NMR spectrum of 4-isobutylstyrene (1). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/64571/64571fig05.jpg" /> 
Figure 5: Synthesis of bora-ibuprofen (2) via glovebox and benchtop boracarboxylation methods. The yield of bora-ibuprofen was 62% and 59% by the glovebox and boracarboxylation methods, respectively. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig05large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/64571/64571fig06.jpg" /> 
Figure 6: 1H NMR spectrum of bora-ibuprofen (2). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig06large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/64571/64571fig07.jpg" /> 
Figure 7: 13C NMR spectrum of bora-ibuprofen (2). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig07large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 8" class="xfigimg" src="/files/ftp_upload/64571/64571fig08.jpg" /> 
Figure 8: 11B NMR spectrum of bora-ibuprofen (2). <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig08large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 9" class="xfigimg" src="/files/ftp_upload/64571/64571fig09.jpg" /> 
Figure 9: Derivatization of bora-ibuprofen. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/64571/64571fig09large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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

Nanyang Technological University

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

Microwave-assisted Intramolecular Dehydrogenative Diels-Alder Reactions for the Synthesis of Functionalized Naphthalenes/Solvatochromic Dyes

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to the preparation of new organic dyes. Although numerous strategies have been reported to access naphthalene scaffolds, many procedures still present limitations in terms of incorporating functionality, which in turn narrows the range of available substrates. The development of versatile methods for direct access to substituted naphthalenes is therefore highly desirable.
The Diels-Alder (DA) cycloaddition reaction is a powerful and attractive method for the formation of saturated and unsaturated ring systems from readily available starting materials. A new microwave-assisted intramolecular dehydrogenative DA reaction of styrenyl derivatives described herein generates a variety of functionalized cyclopenta[b]naphthalenes that could not be prepared using existing synthetic methods. When compared to conventional heating, microwave irradiation accelerates reaction rates, enhances yields, and limits the formation of undesired byproducts.
The utility of this protocol is further demonstrated by the conversion of a DA cycloadduct into a novel solvatochromic fluorescent dye via a Buchwald-Hartwig palladium-catalyzed cross-coupling reaction. Fluorescence spectroscopy, as an informative and sensitive analytical technique, plays a key role in research fields including environmental science, medicine, pharmacology, and cellular biology. Access to a variety of new organic fluorophores provided by the microwave-assisted dehydrogenative DA reaction allows for further advancement in these fields.

Microwave-assisted intramolecular dehydrogenative Diels-Alder (DA) reactions provide concise access to functionalized cyclopenta[b]naphthalene building blocks. The utility of this methodology is demonstrated by one-step conversion of the dehydrogenative DA cycloadducts into novel solvatochromic fluorescent dyes via Buchwald-Hartwig palladium-catalyzed cross-coupling reactions.

Functionalized naphthalenes have applications in a variety of research fields ranging from the synthesis of natural or biologically active molecules to ...

Seeded Synthesis of CdSe/CdS Rod and Tetrapod Nanocrystals

We demonstrate a method for the synthesis of multicomponent nanostructures consisting of CdS and CdSe with rod and tetrapod morphologies. A seeded synthesis strategy is used in which spherical seeds of CdSe are prepared first using a hot-injection technique. By controlling the crystal structure of the seed to be either wurtzite or zinc-blende, the subsequent hot-injection growth of CdS off of the seed results in either a rod-shaped or tetrapod-shaped nanocrystal, respectively. The phase and morphology of the synthesized nanocrystals are confirmed using X-ray diffraction and transmission electron microscopy, demonstrating that the nanocrystals are phase-pure and have a consistent morphology. The extinction coefficient and quantum yield of the synthesized nanocrystals are calculated using UV-Vis absorption spectroscopy and photoluminescence spectroscopy. The rods and tetrapods exhibit extinction coefficients and quantum yields that are higher than that of the bare seeds. This synthesis demonstrates the precise arrangement of materials that can be achieved at the nanoscale by using a seeded synthetic approach.

A protocol for the seeded synthesis of rod-shaped and tetrapod-shaped multicomponent nanostructures consisting of CdS and CdSe is presented.

We demonstrate a method for the synthesis of multicomponent nanostructures consisting of CdS and CdSe with rod and tetrapod morphologies. A seeded ...

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium Under Mild Reaction Conditions

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family of easy accessible, very cheap, and air stable, but highly active and universally applicable C-C cross-coupling catalysts with an excellent functional group tolerance. Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1), the least stable complex within this series towards protons; e.g. in the form of water, allows an eased nanoparticle formation and hence, proved to be the most active Heck catalyst within this series at 100 &#176;C and is a very rare example of an effective and versatile catalyst system that efficiently operates under mild reaction conditions. Rapid and complete catalyst degradation under work-up conditions into phosphonates, piperidinium salts and other, palladium-containing decomposition products assure an easy separation of the coupling products from catalyst and ligands. The facile, cheap, and rapid synthesis of 1,1',1"-(phosphinetriyl)tripiperidine and 1 respectively, the simple and convenient use as well as its excellent catalytic performance in the Heck reaction at 100 &#176;C make 1 to one of the most attractive and greenest Heck catalysts available.
We provide here the visualized protocols for the ligand and catalyst syntheses as well as the reaction protocol for Heck reactions performed at 10 mmol scale at 100 &#176;C and show that this catalyst is suitable for its use in organic syntheses.

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-phosphinetriyltripiperidine]}palladium Under Mild Reaction Conditions

Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium [(P(NC5H10)3)2Pd(Cl)2] (1) is an easy accessible, cheap, and air stable, but highly active Heck catalyst with an excellent functional group tolerance that efficiently operates under mild reaction conditions to give the coupling products in very high yields.

Dichloro-bis(aminophosphine) complexes of palladium with the general formula of [(P{(NC5H10)3-n(C6H11)n})2Pd(Cl)2] (where n = 0-2), belong to a new family ...

Synthesis and Characterization of Functionalized Metal-organic Frameworks

Metal-organic frameworks have attracted extraordinary amounts of research attention, as they are attractive candidates for numerous industrial and technological applications. Their signature property is their ultrahigh porosity, which however imparts a series of challenges when it comes to both constructing them and working with them. Securing desired MOF chemical and physical functionality by linker/node assembly into a highly porous framework of choice can pose difficulties, as less porous and more thermodynamically stable congeners (e.g., other crystalline polymorphs, catenated analogues) are often preferentially obtained by conventional synthesis methods. Once the desired product is obtained, its characterization often requires specialized techniques that address complications potentially arising from, for example, guest-molecule loss or preferential orientation of microcrystallites. Finally, accessing the large voids inside the MOFs for use in applications that involve gases can be problematic, as frameworks may be subject to collapse during removal of solvent molecules (remnants of solvothermal synthesis). In this paper, we describe synthesis and characterization methods routinely utilized in our lab either to solve or circumvent these issues. The methods include solvent-assisted linker exchange, powder X-ray diffraction in capillaries, and materials activation (cavity evacuation) by supercritical CO2 drying. Finally, we provide a protocol for determining a suitable pressure region for applying the Brunauer-Emmett-Teller analysis to nitrogen isotherms, so as to estimate surface area of MOFs with good accuracy.

Synthesis, activation, and characterization of intentionally designed metal-organic framework materials is challenging, especially when building blocks are incompatible or unwanted polymorphs are thermodynamically favored over desired forms. We describe how applications of solvent-assisted linker exchange, powder X-ray diffraction in capillaries and activation via supercritical CO2 drying, can address some of these challenges.

Metal-organic frameworks have attracted extraordinary amounts of research attention, as they are attractive candidates for numerous industrial and ...

Synthesis and Exfoliation of Discotic Zirconium Phosphates to Obtain Colloidal Liquid Crystals

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and engineers. Growth of such anisotropic nanocrystals through a simple chemical method is a challenging task. In this study, we fabricate discotic nanodisks of zirconium phosphate [Zr(HPO4)2&#183;H2O] as a model material using hydrothermal, reflux and microwave-assisted methods. Growth of crystals is controlled by duration time, temperature, and concentration of reacting species. The novelty of the adopted methods is that discotic crystals of size ranging from hundred nanometers to few micrometers can be obtained while keeping the polydispersity well within control. The layered discotic crystals are converted to monolayers by exfoliation with tetra-(n)-butyl ammonium hydroxide [(C4H9)4NOH, TBAOH]. Exfoliated disks show isotropic and nematic liquid crystal phases. Size and polydispersity of disk suspensions is highly important in deciding their phase behavior.

A two dimensional model material of discotic zirconium phosphate was developed. The inorganic crystal with lamellar structure was synthesized by hydrothermal, reflux, and microwave-assisted methods. On exfoliation with organic molecules, layered crystals can be converted to monolayers, and nematic liquid crystal phase was formed at sufficient concentration of monolayers.

Due to their abundance in natural clay and potential applications in advanced materials, discotic nanoparticles are of interest to scientists and ...

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 ...

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. Their synthesis by conventional organic chemistry often requires tedious multi-step synthesis processes, with difficult control of the stereochemical outcome. We present a protocol to enzymatically synthetize amino alcohols starting from the readily available L-lysine in 48 h. This protocol combines two chemical reactions that are very difficult to conduct by conventional organic synthesis. In the first step, the regio- and diastereoselective oxidation of an unactivated C-H bond of the lysine side-chain is catalyzed by a dioxygenase; a second regio- and diastereoselective oxidation catalyzed by a regiodivergent dioxygenase can lead to the formation of the 1,2-diols. In the last step, the carboxylic group of the alpha amino acid is cleaved by a pyridoxal-phosphate (PLP) decarboxylase (DC). This decarboxylative step only affects the alpha carbon of the amino acid, retaining the hydroxy-substituted stereogenic center in a beta/gamma position. The resulting amino alcohols are therefore optically enriched. The protocol was successfully applied to the semipreparative-scale synthesis of four amino alcohols. Monitoring of the reactions was conducted by high performance liquid chromatography (HPLC) after derivatization by 1-fluoro-2,4-dinitrobenzene. Straightforward purification by solid-phase extraction (SPE) afforded the amino alcohols with excellent yields (93% to &#62;95%).

Chiral amino alcohols are versatile molecules for use as scaffolds in organic synthesis. Starting from L-lysine, we synthesize amino alcohols by an enzymatic cascade reaction combining diastereoselective C-H oxidation catalyzed by dioxygenase followed by cleavage of the carboxylic acid moiety of the corresponding hydroxyl amino acid by a decarboxylase.

Amino alcohols are versatile compounds with a wide range of applications. For instance, they have been used as chiral scaffolds in organic synthesis. ...

Chemical Synthesis of Porous Barium Titanate Thin Film and Thermal Stabilization of Ferroelectric Phase by Porosity-Induced Strain

Barium titanate (BaTiO3, hereafter BT) is an established ferroelectric material first discovered in the 1940s and still widely used because of its well-balanced ferroelectricity, piezoelectricity, and dielectric constant. In addition, BT does not contain any toxic elements. Therefore, it is considered to be an eco-friendly material, which has attracted considerable interest as a replacement for lead zirconate titanate (PZT). However, bulk BT loses its ferroelectricity at approximately 130 &#176;C, thus, it cannot be used at high temperatures. Because of the growing demand for high-temperature ferroelectric materials, it is important to enhance the thermal stability of ferroelectricity in BT. In previous studies, strain originating from the lattice mismatch at hetero-interfaces has been used. However, the sample preparation in this approach requires complicated and expensive physical processes, which are undesirable for practical applications.
In this study, we propose a chemical synthesis of a porous material as an alternative means of introducing strain. We synthesized a porous BT thin film using a surfactant-assisted sol-gel method, in which self-assembled amphipathic surfactant micelles were used as an organic template. Through a series of studies, we clarified that the introduction of pores had a similar effect on distorting the BT crystal lattice, to that of a hetero-interface, leading to the enhancement and stabilization of ferroelectricity. Owing to its simplicity and cost effectiveness, this fabrication process has considerable advantages over conventional methods.

Here, we present a protocol for the synthesis of porous barium titanate (BaTiO3) thin film by a surfactant-assisted sol-gel method, in which self-assembled amphipathic surfactant micelles are used as an organic template.

Barium titanate (BaTiO3, hereafter BT) is an established ferroelectric material first discovered in the 1940s and still widely used because of its ...

Synthesis and Structure Determination of &#181;-Conotoxin PIIIA Isomers with Different Disulfide Connectivities

Peptides with a high number of cysteines are usually influenced regarding the three-dimensional structure by their disulfide connectivity. It is thus highly important to avoid undesired disulfide bond formation during peptide synthesis, because it may result in a completely different peptide structure, and consequently altered bioactivity. However, the correct formation of multiple disulfide bonds in a peptide is difficult to obtain by using standard self-folding methods such as conventional buffer oxidation protocols, because several disulfide connectivities can be formed. This protocol represents an advanced strategy required for the targeted synthesis of multiple disulfide-bridged peptides which cannot be synthesized via buffer oxidation in high quality and quantity. The study demonstrates the application of a distinct protecting group strategy for the synthesis of all possible 3-disulfide-bonded peptide isomers of &#181;-conotoxin PIIIA in a targeted way. The peptides are prepared by Fmoc-based solid phase peptide synthesis using a protecting group strategy for defined disulfide bond formation. The respective pairs of cysteines are protected with trityl (Trt), acetamidomethyl (Acm), and tert-butyl (tBu) protecting groups to make sure that during every oxidation step only the required cysteines are deprotected and linked. In addition to the targeted synthesis, a combination of several analytical methods is used to clarify the correct folding and generation of the desired peptide structures. The comparison of the different 3-disulfide-bonded isomers indicates the importance of accurate determination and knowledge of the disulfide connectivity for the calculation of the three-dimensional structure and for interpretation of the biological activity of the peptide isomers. The analytical characterization includes the exact disulfide bond elucidation via tandem mass spectrometry (MS/MS) analysis which is performed with partially reduced and alkylated derivatives of the intact peptide isomer produced by an adapted protocol. Furthermore, the peptide structures are determined using 2D nuclear magnetic resonance (NMR) experiments and the knowledge obtained from MS/MS analysis.

Cysteine-rich peptides fold into distinct three-dimensional structures depending on their disulfide connectivity. Targeted synthesis of individual disulfide isomers is required when buffer oxidation does not lead to the desired disulfide connectivity. The protocol deals with the selective synthesis of 3-disulfide-bonded peptides and their structural analysis using NMR and MS/MS studies.

Peptides with a high number of cysteines are usually influenced regarding the three-dimensional structure by their disulfide connectivity. It is thus ...

Solid-phase Synthesis of [4.4] Spirocyclic Oximes

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of solid-phase synthesis, regenerating Michael (REM) linker strategies, and 1,3-dipolar cycloaddition, a library of structurally similar heterocycles, both with and without a spirocyclic center, can be constructed. The main advantages of the solid-support synthesis are as follows: first, each reaction step can be driven to completion using a large excess of reagents resulting in high yields; next, the use of commercially available starting materials and reagents keep the costs low; finally, the reaction steps are easy to purify via simple filtration. The REM linker strategy is attractive because of its recyclability and traceless nature. Once a reaction scheme is completed, the linker can be reused multiple times. In a typical solid-phase synthesis, the product contains either a part of or the whole linker, which can prove undesirable. The REM linker is &#34;traceless&#34; and the point of attachment between the product and the polymer is indistinguishable. The high diastereoselectivity of the intramolecular 1,3-dipolar cycloaddition is well documented. Limited by the insolubility of the solid support, the reaction progression can only be monitored by a change in the functional groups (if any) via infrared (IR) spectroscopy. Thus, the structural identification of intermediates cannot be characterized by conventional nuclear magnetic resonance (NMR) spectroscopy. Other limitations to this method stem from the compatibilities of the polymer/linker to the desired chemical reaction scheme. Herein we report a protocol that allows for the convenient production of spirocyclic heterocycles that, with simple modifications, can be automated with high-throughput techniques.

Here we present a protocol to demonstrate an efficient method for the synthesis of spirocyclic heterocycles. The five-step process utilizes solid-phase synthesis and regenerating Michael linker strategies. Generally difficult to synthesize, we present a customizable method for the synthesis of spirocyclic molecules otherwise inaccessible to other modern approaches.

A convenient synthetic route for spirocyclic heterocycles is well sought after due to the molecule&#39;s potential use in biological systems. By means of ...

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

Summary

Explore More Videos

Chapters in this video

Microwave-assisted Intramolecular Dehydrogenative Diels-Alder Reactions for the Synthesis of Functionalized Naphthalenes/Solvatochromic Dyes

Seeded Synthesis of CdSe/CdS Rod and Tetrapod Nanocrystals

Mizoroki-Heck Cross-coupling Reactions Catalyzed by Dichloro{bis[1,1',1''-(phosphinetriyl)tripiperidine]}palladium Under Mild Reaction Conditions

Synthesis and Characterization of Functionalized Metal-organic Frameworks

Synthesis and Exfoliation of Discotic Zirconium Phosphates to Obtain Colloidal Liquid Crystals

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

Enzymatic Cascade Reactions for the Synthesis of Chiral Amino Alcohols from L-lysine

Chemical Synthesis of Porous Barium Titanate Thin Film and Thermal Stabilization of Ferroelectric Phase by Porosity-Induced Strain

Synthesis and Structure Determination of µ-Conotoxin PIIIA Isomers with Different Disulfide Connectivities

Solid-phase Synthesis of [4.4] Spirocyclic Oximes