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 mix...

<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. 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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 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 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 ...

This protocol provides a facile route to synthesize a novel bora-ibuprofen derivative with moderate yield in two steps using conventional benchtop chemistry, and without needing a nitrogen filled glove box. The tandem cross-coupling and copper-catalyzed work of oxylation protocols can be applied to various alpha-substituted and unsubstituted styrene derivatives. Purifying bora-ibuprofen using the described aqueous workup can be difficult.Occasionally, trace and purities will remain after the purification. If necessary, one or more recrystallizations will remove these trace impurities. Begin to synthesize 4-isobutylstyrene via Suzuki cross-coupling by adding palladium tetrakistriphenylphosphine and anhydrous potassium carbonate into a 40-milliliter scintillation vial containing a magnetic stir bar.Seal the vial with a pressure relief cap and encapsulate the vial seal completely using electrical tape before purging the reaction mixture with argon for two minutes. Then add one bromo-4-isobutylbenzene to the vial followed by anhydrous tetrahydrofuran obtained from a solvent purification system with continuous argon flow, and commence magnetic stirring. Next, add argon sparged deionized water and vinylboronic acid pinacol ester to the reaction mixture.Purge the reaction mixture with argon for five minutes. Once the purging is over, heat the reaction mixture on a stirring hot plate at 85 degrees Celsius for 24 hours. To ensure completion of the reaction after 24 hours, remove a small aliquot from the reaction mixture.Dilute it with two milliliters of dichloromethane, and perform thin-layer chromatography using hexane. Upon the confirmation of reactant consumption by TLC, add the reaction mixture to a 125-milliliter separatory funnel, followed by the addition of 30 milliliters of deionized water. Now, perform extraction with five milliliters of dichloromethane three times, and combine the organic extracts into a 125-milliliter Erlenmyer flask.Discard the aqueous layer. Transfer the combined organic extracts into a 125-milliliter separatory funnel, and wash it with 30 milliliters of brine. After transferring the organic layer into a separate 125-milliliter Erlenmyer flask, mix it with five grams of sodium sulfate and swirl the flask for at least 20 seconds.Use a Buchner funnel to vacuum filter the solution into a 125-milliliter filter flask. Concentrate the filtrate in a 100-milliliter round bottom flask by applying vacuum until a pale yellow viscous oil is produced. To obtain pure 4-isobutylstyrene, purify the crude product by column chromatography using 100%hexane as the eluent.To synthesize bora-ibuprofen from 4-isobutylstyrene, add N, N dicyclohexyl-imidazolium chloride and sodium tertiary-butoxide into a 40-milliliter scintillation vial containing a magnetic stir bar. Seal the vial with an airtight septum and immediately purge it with argon for five minutes. Now, using a syringe, add 20 milliliters of anhydrous and degassed tetrahydrofuran into the scintillation vial containing the mixture of ligand and base.Stir the resulting solution for an additional 30 minutes after purging it with argon for five minutes. Meanwhile, carefully add 119 milligrams of cupric chloride into another 40-milliliter scintillation vial containing a magnetic stir bar. Seal it with an airtight septum and immediately purge the vial with argon for five minutes.After stirring for 30 minutes, transfer the ligand solution to the scintillation vial containing cupric chloride under a positive argon flow. Stir the resulting solution for one hour to generate the catalyst. In a 500-milliliter round bottom flask containing a magnetic stir bar, Add 5.08 grams of bis(pinacolato)diboron.Seal the flask properly and add 140 milliliters of THF and 1.8 milliliters of 4-isobutylstyrene into the flask before purging it with argon for five minutes. Then immediately purge the round bottom flask with bone-dry carbon dioxide. Slowly add the catalyst solution into it for about 30 seconds, and continue purging with bone-dry carbon dioxide for 15 minutes before keeping the reaction stirring at ambient temperature for 16 hours.Upon completion of the reaction, concentrate the mixture for 15 to 30 minutes under vacuum, followed by acidifying it with 30 milliliters of 1-Molar aqueous hydrochloric acid. Then add 50 milliliters of diethyl ether to the acidified reaction mixture and swirl the solution for 10 seconds before transferring it to a 500-milliliter separatory funnel. Separate the organic and aqueous layers and add the aqueous layer to a one-liter Erlenmyer flask.Extract the organic layer eight times with 50 milliliters of saturated sodium bicarbonate, and transfer the aqueous extracts into a separate one-liter Erlenmyer flask. Slowly and carefully acidify the combined aqueous extract with 12-Molar hydrochloric acid, and transfer the solution to a clean 500-milliliter separatory funnel. Extract the aqueous solution eight times with 50 milliliters of dichloromethane.Transfer the organic extracts into a clean one-liter Erlenmyer flask, and add 50 grams of sodium sulfate to the organic extract and swirl the flask for 20 seconds. Next, filter the solution through a Buchner funnel and collect it in a clean 1000-milliliter filtration flask before transferring the filtrate to a round bottom flask to concentrate it under vacuum. Dissolve the residue in 10 milliliters of HPLC-Grade heptane, and store it in a 20 degree Celsius freezer overnight to produce pure recrystallized bora-ibuprofen.The described synthesis protocol reliably produced 4-isobutylstyrene with 89%yield. Whereas the yield for benchtop synthesis of bora-ibuprofen was found to be 59%The proton NMR spectrum of 4-isobutyl styrene showed AMX splitting, a signature of monosubstituted styrene derivatives. The resonances appeared as a doublet at 5.17 ppm, another doublet at 5.69 ppm, and a doublet of doublets at 6.62 to 6.78 ppm.Another characteristic feature was the isobutylmethane proton appearing as a nonet at 2.37 to 2.52 ppm, with corresponding methyl groups at 0.89 ppm. The nine resonances observed in the 13 C-NMR spectrum of 4-isobutylstyrene were also in good agreement with its structure. The proton-NMR spectrum of bora-ibuprofen showed the characteristic ABX splitting pattern.The A and B resonances appeared as a doublet of doublets at 1.53 and 1.29 ppm, while the X resonance appeared at 3.82 ppm. The 13-C-NMR spectrum of bora-ibuprofen showed a broad signal at 16 ppm, indicative of a quadrupolar broadened carbon bound to boron. Another significant resonance was at 180.8 ppm corresponding to the carbonyl carbon of the free carboxyl acid group.The 11-B-NMR spectrum showed a single broad resonance at 33.4 ppm, indicative of a trivalent boronic ester. Properly encapsulating the pressure release of vial cap is important to prevent air or moisture from entering. Also, sufficiently pure grade gaseous carbon dioxide should be used, specifically 99.8%or bone dry.This technique provides access to unique bora-ibuprofen in similar products that could now be functionalized through the carboxylic acid, or the boron functional groups.

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2.4K Views.  West Virginia University. Questo protocollo fornisce un percorso facile per sintetizzare un nuovo derivato del bora-ibuprofene con una resa moderata in due fasi utilizzando la chimica da banco convenzionale e senza bisogno di un vano portaoggetti riempito di azoto. L'accoppiamento incrociato tandem e il lavoro catalizzato dal rame dei protocolli di ossilazione possono essere applicati a vari derivati dello stirene alfa-sostituiti e non sostituiti. Purificare il bora-ibuprofene usando il workup acquoso descritto può e...